Peptide microparticle compositions and related methods

Abstract

The invention herein provides pharmaceutically acceptable, controlled-release microparticle composition(s) and formulation(s) comprising such composition(s) for use in the treatment of obesity, diabetes, or both. Composition(s) and formulation(s) herein comprise microparticles comprising API(s) and biodegradable polymer compound(s). API(s) of composition(s) and formulation(s) herein demonstrate detectable or significant agonist activity against one or more of melanocortin-1 receptor (MC1), melanocortin-2 receptor (MC2), melanocortin-3 receptor (MC3), melanocortin-4 receptor (MC4), and melanocortin-5 receptor (MC5), GLP-1 receptor, glucagon receptor, and GIP receptor and typically have a molecular weight of at least about 1000 Da.

Description

PEPTIDE MICROPARTICLE COMPOSITIONS AND RELATED METHODSFIELD OF THE INVENTION

[0001] The invention primarily relates to stable, long-acting release microparticle (e.g., microsphere) formulations containing melanocortin receptor agonist active pharmaceutical ingredients or similar / related API molecules (in terms of structure, effect, or both) which is an agonist at one or more of melanocortin- 1 (MCI); melanocortin-2 (MC2); melanocortin-3 (MC3); melanocortin-4 (MC4); or melanocortin-5 (MC5) receptor or incretin hormone agonist active pharmaceutical ingredients or similar / related API molecules (in terms of structure, effect, or both), which is an agonist at one or more of glucagon-like peptide-1 (GLP-1), glucagon receptor , glucose-dependent insulino-tropic polypeptide (GIP), or combinations thereof, and methods of their use in the treatment of obesity.BACKGROUND OF THE INVENTION

[0002] Excess body weight (“overweight”) and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) over 25 is considered overweight, and over 30 is considered obese. The issue of overweight and obesity has grown to epidemic proportions globally, with over 4 million people dying each year as a result of being overweight or obese (2017 data). At the time of this submission, more people are obese than underweight in every region except sub-Saharan Africa and Asia. Once considered a problem only in high-income countries, overweight and obesity are now dramatically on the rise in low- and middle-income countries, particularly in urban settings. The vast majority of overweight or obese children live in developing countries, where the rate of increase has been more than 30% higher than that of developed countries.

[0003] Overweight and obesity are major risk factors for a number of chronic diseases, including cardiovascular diseases such as heart disease and stroke which are the leading causes of death worldwide. Excess weight can lead to musculoskeletal disorders including osteoarthritis, with obesity further being associated with some cancers, including endometrial, breast, ovarian, prostate, liver, gallbladder, kidney and colon cancer.

[0004] Although other factors are involved, the fundamental cause of obesity is an imbalance of calories consumed and calories expended. As global diets have changed in recent decades, there has been an increase in the consumption of energy-dense foods high in fat and free sugars. There has also been a decrease in physical activity due to the changing nature of many types of work, more access to transportation and increased urbanization.

[0005] Type 2 diabetes primarily occurs as a result of obesity and lack of exercise. Some people are genetically more at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to type 1 diabetes and gestational diabetes. Thus being overweight can lead to diabetes and associated conditions, including blindness, limb complications (often leading to amputation(s)), and a need for dialysis. Rates of diabetes have quadrupled globally since 1980. The risk of diabetes and other noncommunicable diseases described above increases even when a person is only slightly overweight and grows more serious as the body mass index (BMI) climbs.

[0006] Apart from dietary changes and performing exercise a current such treatment protocols involves the weekly subcutaneous dosing of a drug product such as U.S. Food and Drug Administration (FDA) approved Semaglutide (WEGOVY) injection for chronic weight management in adults with obesity or overweight status and at least one weight-related condition.

[0007] Recently U.S. Food and Drug Administration (FDA) has also approved the tirzepatide (MOUNJARO™) once weekly subcutaneous injection to improve glycemic control in adults with type 2 diabetes mellitus and ZEPBOUND™ (tirzepatide) once weekly subcutaneous injection as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults.

[0008] Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It contains a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucosedependent manner.

[0009] GLP-1 is a physiological regulator of appetite and caloric intake. Nonclinical studies suggest the addition of GIP may further contribute to the regulation of food intake. Both GIP receptors and GLP-1 receptors are found in areas of the brain involved in appetite regulation. Animal studies show that tirzepatide distributes to and activates neurons in brain regions involved in regulation of appetite and food intake.

[0010] Setmelanotide (IMCIVREE®) once daily subcutaneous injection is another U.S. Food and Drug Administration (FDA) approved product for chronic weight management.

[0011] MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. Based on nonclinical evidence, setmelanotide may re-establish MC4 receptor pathway activity to reduce food intake and promote weight loss through decreasedcaloric intake and increased energy expenditure in patients with obesity due to POMC, PCSK1, or LEPR deficiency, or BBS associated with insufficient activation of the MC4 receptor.

[0012] Multiple ways of addressing burst release have been presented by those skilled in the art, such as, for example, embedding ionic groups, fatty acids, or amines into the microspheres of such compositions. Such approaches result in these extra compounds being injected into the human body and, accordingly, potential toxicity assessments must be considered and performed. WOO 1 / 78687 to Lee describes composition(s) comprising biodegradable, porous microspheres, having accessible ionic functional groups, and a biopharmaceutical incorporated therein, and process(es) for preparing the same.US2023 / 0014750 to Zats describes semaglutide depot formulations for the treatment of type-2 diabetes mellitus, obesity, and Parkinson’s disease.

[0013] All products for the treatment of weight management, obesity and type 2 diabetes mellitus are administered on either a daily or a weekly basis. Frequent administration of injection is inconvenient to the patient. No presently marketed product providing a burst-limited, controlled release of active pharmaceutical ingredient(s) is available to treat the growing global population of diabetes sufferers and obese patients. Provision of the same while avoiding administration of additional compounds into the body as constituent s) of such compositions will require significant inventive ingenuity.CONSTRUCTION AND TERMS (CONSTRUCTION PRINCIPLES AND DESCRIPTION OF SELECT TERMS)

[0014] This section offers guidelines and resources intended to aid readers in understanding this disclosure.General Terms and Principles

[0015] The intended audience for this disclosure (“readers”) are persons having at least ordinary skill(s) in the practice of technologies discussed or used herein. Readers may also be called “skilled persons,” and such technologies and related publicly available prior knowledge are collectively referred to as “the art.” Terms such as “understood,” “known,” and “ordinary meaning” refer to the general knowledge of skilled persons.

[0016] The purpose of this document (“disclosure”) is to describe a number of new technologies (sometimes just called the “technology” and each discrete embodiment of which sometimes being called “a technology”) and to provide readers with the ability to practice such technologies (e.g., by exemplification, by description of elements thereof and relationship(s) ofsuch elements to each other, and possibly other means). Readers will understand from this disclosure whether the technology / technologies include different forms, e.g., objects (such as systems, compositions, or devices), methods, or both, as will be clear from the disclosure. Disclosed technologies may be associated with surprising, unexpected, or otherwise inventive properties and, accordingly, in many cases, a described technology may reflect an invention.

[0017] The term “uncontradicted” means not contradicted by this disclosure, logic, or plausibility, the latter two elements being based on the knowledge of skilled persons.

[0018] Disclosed here are several different but related exemplary aspects (variations) of the technology(ies) (also referred to as, e.g., “cases,” “facets,” “respects,” or “embodiments”). The disclosure encompasses all such aspects as described individually and as can be arrived at by any combination of such individual aspects. Thus, uncontradicted, any reference to “aspects” (e.g., “according to aspects” or “in an aspect”) will be understood as referring to according to any of the other suitable aspects of the technology(ies) described herein. In this respect, the breadth and scope of the disclosure should not be limited by any exemplary aspect(s) / embodiment(s) herein. No language in this disclosure should be construed as indicating any element / step is essential to the practice of any technology or group of technologies provided by this disclosure unless such a requirement is explicitly stated. Uncontradicted, any aspect(s) described in any part of this disclosure can be combined with any other aspect(s) in any other part. Readers will discern that the term “aspect” also is used sometimes to refer to portions of this disclosure and, in such respects is used in a manner similar to “subject” or “topic.”

[0019] Uncontradicted, all technical / scientific terms used here should be read, at least in one aspect, to have the same meanings as commonly understood by skilled persons, regardless of any narrower examples or descriptions provided here (including any term introduced initially in quotations). However, readers will also recognize that some aspects can be characterized by the inclusion of elements, steps, features, characteristics, etc., associated with specific descriptions provided here and that such specific disclosures represent distinct embodiments of the disclosure apart from the corresponding aspect that is provided by interpreting the relevant aspect using any broader commonly used terminology or concept. Uncontradicted, disclosure of any aspect using known terms, which terms are narrowed by example or otherwise, implicitly discloses one or more related aspects in which the applicable terms are alternatively interpreted using the broadest reasonable interpretation of skilled persons.

[0020] Uncontradicted, the term “or” means “and / or” here, regardless of any inclusion of the actual phrase “and / or” (e.g., phrases such as “A, B, or C” and “A, B, and / or C” each simultaneously discloses aspects including (1) all of A, B, and C; (2) A and C; (3) A and B; (4) B and C; (5) only A; (6) only B; and (7) only C (and also support sub-groupings, such as “A or B,” “A or C,” etc.)). Uncontradicted the use of a modifier / term such as “or both” in connection with elements (e.g., “element A, element B, or both”) does not mean or imply that elements listed only as “A or B” do not include combinations of A and B.

[0021] For conciseness, symbols are used where appropriate. E.g.,is used for “and,” & for “about.” Symbols such as < and > are given their ordinary meaning (e.g., “<” means “less than or equal to” & “>” means “greater than or equal to”). A slash “ / ” between terms here can represent “or” (“A / B” means “A or B”) or identify synonyms of an element, depending on context. The inclusion of “(s)” after an element or a step indicates that >1 of such an element is present, step performed, and the like. E.g., “element(s)” refers to both 1 element and >2 elements, with the understanding that each thereof is an independent aspect of the disclosure.

[0022] Uncontradicted, the term “also” means “also or alternatively.” Uncontradicted, the terms “here” & “herein” mean “in this disclosure.” The abbreviation “z.a” (alternatively “ia” or “zrz”) means “inter alia" or “(possibly) among other things.” “Also known as” is abbreviated “aka,” “AKA,” “a.k.a” (and can also or alternatively mean “is otherwise referred to here,” even if the relationship between the terms is not well known). The similar abbreviation “aka / ac” means “also known as or otherwise called” is sometimes alternatively used to stress this point about the nature of the acronym. Uncontradicted, the term “elsewhere” means “elsewhere herein.”

[0023] Use of the abbreviation “etc.” (or “et cetera”) in association with a list of elements / steps means any or all suitable combinations of the recited elements / steps or any known equivalents of such recited elements / steps for achieving the function(s) of such elements / steps known in the art. Readers should interpret phrases like “and the like” similarly.

[0024] Uncontradicted, terms such as “and combinations,” “or combinations,” and “combinations thereof,” etc., regarding listed elements / steps, means any or all possible / suitable combinations of the associated elements / steps. Thus, e.g., uncontradicted, a phrase like “combination of any thereof’ refers to any or all combinations.

[0025] Aspects may be described as suitable for method(s) / use(s) disclosed herein. Uncontradicted, terms such as “suitable” or “suitability” mean acceptable, appropriate, or, in aspects practical for performing a particular function / achieving particular state(s) / outcome(s),and typically means effective, practical, and non-deleterious / harmful to associated valuable subject matter (human health, resource state, etc.). E.g., uncontradicted, the term “suitable” means appropriate, acceptable, or in contexts sufficient, or providing at least generally or substantially all an intended function (of the element or overall whole of the aspect), without causing or imparting significant negative / detrimental impact. Uncontradicted, each method step, component / ingredient, or result element of the technical aspects of this disclosure should be understood to implicitly be mostly, generally only, substantially only, or only of an amount, degree, or character suitable in connection with its intended function, the intended function of the associated whole, or both. In some respects, suitability can be demonstrable through scientific studies and to a degree of significance through suitable tests / measures such as scientific tests, well-controlled and adequate studies (e.g., clinical studies), adequately powered trials, etc.

[0026] Steps, elements, compositions, devices, components, and the like also or alternatively can be characterized as being “effective.” Uncontradicted, any disclosed element is to be construed as being effective for its intended purpose and present in an effective amount, and any step performed is to be understood as being performed / applied effectively, such as in an effective amount or an effective number of times, etc. Uncontradicted efficacy can be judged by evaluating the element(s) ability to perform or contribute to the described function(s) or characteristic(s) associated with the component, device, step, etc., the overall aspect, or both in any manner disclosed here, known in the art, or both. For example, when applied to effects in organisms, such as people, efficacy and similar terms uncontradicted should be interpreted to at least implicitly disclose efficacy that can be measured (1) in a treated subject, (2) in a majority of subjects in a population, (3) in a statistically significant number of subjects in a population, (4) generally all subjects in a population, (5) substantially all subjects in a population, or (6) in a statistically significant number of or more of a typical or average subject of the class of subjects treated. Object elements or steps are, uncontradicted, understood to be implicitly present in “effective amount,” and, uncontradicted, any described class of object or step in connection with a device, system, composition, or method, is understood to be present in the associated whole or performed in association with the associated entire method in an effective amount, effective way, or having effective characteristic(s), which generally means, an amount that the described object / component or step is effective for the described function(s) associated with the element, associated whole, or both. A “step” is not necessarily a general “step for” performing a function.

[0027] Uncontradicted, heading(s) (e.g., “Construction and Terms”) and subheadings used here are included for convenience and do not limit the scope of any aspect(s). Uncontradicted, aspect(s), step(s), or element(s) described under one heading can apply to other aspect(s) or step(s) / element(s) here.

[0028] Ranges of values here represent each value falling within a range within an order of magnitude of the smallest endpoint of the range without having to write each value of the range explicitly. E.g., a recited range of 1-2 implicitly discloses each of 1.0, 1.1, 1.2, ... 1.9, and 2.0, and 10-100 implicitly discloses each of 10, 11, 12, ... 98, 99, and 100). Uncontradicted, all ranges include the range's endpoints, regardless of how a range is described. E.g., “between 1-5” includes 1 and 5 in addition to 2, 3, and 4 (and all numbers between such numbers within an order of magnitude of such endpoints, e.g., 1.0, 1.1, ... 4.9, and 5.0). For the avoidance of doubt, any number within a range, regardless of the order of magnitude of the number, is covered by the range (e.g., a range of 2-20 covers 18.593). Uncontradicted, readers will understand that any two values in a range provided as a list herein can be combined as endpoints to form a range defining a more particular aspect of the disclosure (e.g., if a list of values 1, 2, 3, 4, and 5 of element X is provided, readers will understand that the disclosure implicitly discloses an aspect comprising 2-4 X, 3-5 X, and 1-3 X, etc.

[0029] Terms of approximation (e.g., “about,” or “approximately”) can be used here (1) to refer to a set of related values or (2) where a precise value is difficult to define (e.g., due to limits of measurement). Uncontradicted, all exact values provided here simultaneously / implicitly disclose corresponding approximate values and vice versa (e.g., disclosure of “about 10” provides explicit support for the use of 10 exactly in such aspect / description). Ranges described with approximate value(s) include all values encompassed by each approximate endpoint, regardless of presentation (e.g., “about 10-20” has the same meaning as “about 10 - about 20”). The scope of value(s) encompassed by an approximate term typically depends on the context of the disclosure, criticality or operability, statistical significance, understanding of the art, etc. In the absence of guidance here or in the art for an element, terms such as “about” when used in connection with an element should be interpreted as ± 10% of the indicated value(s) and implicitly disclosing ± 5%, ± 2%, ± 1%, and ± 0.5%. Two or more values may be characterized as approximately similar if they would be considered to be about the same on such bases.

[0030] Aspects may be associated with description of change or difference. In some cases, similarity or difference can be assessed as similar or not (i.e., statistically similar ordifferent). In cases, a difference or change means a “sizable” change or difference, which means a change or difference that is beyond what would be considered substantially the same or approximately the same (approximately or about in such contexts being either defined in the art or + / - 10% or being recognized by readers as not having different characteristics or outcomes that are substantially different with respect to intended function) (e.g., a change of >12.5%, >15%, >20%, etc., such as 12.5%-50%, 12.5%-33%, 15-45%, etc., or 15-150%, 20-200%, 30- 300%, etc.). In aspects, a change or difference in element(s) can be characterized as a “major” change or difference, which means a change or difference that is an increase or decrease (1) of at least 33% and can be a change of at least 50%, at least 75%, at least 100%, at least 150%, at least 200% (2x), e.g., at least 0.5x - 5x, lOx, or 20x or (2) by one or more (e.g., 2 or 3) order(s) of magnitude. Uncontradicted, elements, compositions, outcomes, etc., described as different herein or described as different in any of these ways provide implicit support for corresponding aspects in which the applicable change / difference is characterized as one of the other differences. The modifier “constrained” means that a value, such as a sizable value, a detectable value, or a major value is limited to 50% or less of a whole (e.g., 45% or less, 40% or less, 37.5% or less, or 35% or less of a whole). Uncontradicted, any disclosure of such a term herein provides implicit support for an otherwise corresponding aspect in which the scope of the applicable value can be characterized as a constrained value.

[0031] This disclosure includes aspects of the technology that are associated with particular characteristics, such as amounts of components (or ranges thereof), In cases, several such characteristics of varying scope may be provided. Readers will understand that each such characteristic can be associated with particular properties that distinguish such aspects from other aspects, and, accordingly, each such range can be viewed as critical to a particular aspect of the technology, even if the associated results, properties, functions, etc., associated with such aspects are not directly / explicitly communicated in association with any such characteristics.

[0032] Lists of aspects, elements, steps, and features are sometimes employed for conciseness. Unless indicated, each member of each list should be viewed as an independent aspect. Each aspect defined by any individual member of a list can have and often will have, nonobvious properties vis-a-vis aspects characterized by other members of the list.

[0033] Uncontradicted, the terms “a” and “an” and “the” and similar referents encompass both the singular and the plural form of the referenced element, step, or aspect. Uncontradicted, terms in the singular implicitly convey the plural and vice versa herein (in other words, disclosure of an element / step implicitly discloses the corresponding use of such / similarelements / steps and vice versa). Hence, e.g., a passage regarding an aspect including X step supports a corresponding aspect including several X steps. Uncontradicted, any mixed use of a referent such as “a” in respect of one element / step or characteristic and “one or more of’ concerning another element / step or characteristic in a paragraph, sentence, aspect, or claim, does not change the meaning of such referents. Thus, for example, if a paragraph describes a composition comprising “an X” and “one or more Ys,” the paragraph should be understood as providing disclosure of “one or more Xs” and “one or more Ys.”

[0034] “Significant” and “significantly” mean results / characteristics that are statistically significant using >1 appropriate test(s) / trial(s) in the given context (e.g., p < 0.05 / 0.01). “Detectable” means measurably present / different using known detection tools / techniques. The acronym “DOS” (or “DoS”) means “detectable(ly) or significant(ly).” The term “measurably” means at a measurable level and, uncontradicted, comprises at a suitable measurable level / amount. The term detectable provides implicit disclosure for aspects that are “measurable,” and the term “measurable” implicitly supports aspects where the measured or measurable element is “detectable.” Uncontradicted, any aspect including an element described as “similar” to another element implicitly discloses, at least as one aspect, where the similarity comprises statistical similarity. Uncontradicted, any reference to a comparison, change, or other relationship between elements (e.g., a result) characterized by similarity or detectability also implicitly discloses changes or comparisons where the difference is approximately / about the same (e.g., within + / - 10% of each other).

[0035] Uncontradicted, any value provided here that is not accompanied by a unit of measurement (e.g., a weight of 50 or a length of 20), either any previously provided unit for the same element / step or the same type of element / step will apply, or, in cases where no such disclosure exists, the unit most used in association with such an element / step in the art applies.

[0036] Herein certain measured “amount(s)” may be referenced or expressed as “concentration(s)” or vice versa. For example, a unit such as percent-by-weight (expressed as, e.g., wt.%) may be referenced as a concentration. Uncontradicted, the use of such units (e.g., wt.%) should be understood as carrying the meaning as typically understood in the art regardless of whether such unit is referenced as a concentration or an amount. Readers will understand that the disclosure of concentrations / amounts of different elements / components acts as a disclosure of compositions characterized by relationships in such amounts formed between such elements / components. Accordingly, uncontradicted, any disclosure of amounts / concentrations that reflects a suitable relationship between elements / components provides an implicit disclosureof a composition that varies from the specifically disclosed amounts / concentrations, but which retains the relationship. For example, if the disclosure provides for the inclusion of 1 unit of A and 3 units of B in an aspect, readers will understand that this means that the disclosure implicitly provides a corresponding aspect characterized by the inclusion of suitable amounts of A and B, wherein such amounts are present in a ratio of about 1 part A to about 3 parts B.

[0037] Uncontradicted, the terms “including,” “containing,” “comprising,” and “having” mean “including, but not limited to,” or “including, without limitation.” Uncontradicted, use of terms such as comprising and including regarding elements / steps means including any detectable number or amount of an element or including any detectable performance of a step / number of steps (with or without other elements / steps). Uncontradicted, “a” means one or more, even when terms such as “one or more” or “at least one” are used in association with the referent “a.”

[0038] For conciseness, description of an aspect “comprising” or “including” an element, concerning a collection / whole (e.g., a system, device, or composition), implicitly provides support for any detectable amount / number, such as, e.g., between a detectable or measurable amount and about 33%, such as, e.g., >~1%, >~5%, >~10%, >~20%, >~25%, or >~33%, as in, for example, -0.00001% - -33%, -1% - -33%, -5% - -33%, -10% - -33%, -15% - -33%, -20% - -33%, -25% - -33%, or, e.g., -30% - -33%.

[0039] In certain respects, description of an aspect “comprising” or “including” an element concerning a collection / whole implicitly provides support for amounts greater than about 33%, such as, e.g., -50% - -75%, such as, e.g., >~50%, >—51%, >—51%, >~66%, or >~70%, such as, e.g., -55% - -75%, -60% - -75%, or -70% - -75%, such as, e.g., -35%, -40%, or -45%.

[0040] In still further respects, description of an aspect “comprising” or “including” an element concerning a collection / whole implicitly provides support for amounts greater than about 80%, such as, e.g., -80%, -85%, >~90%, -93%, >~95%, >~99%, or -100% of the whole / collection being made up of the element, as in, e.g., -77% or more, or essentially all of the whole / collection being made up of the element (i.e., that the collection consists essentially of the referenced element). Similarly, a method described as including a step concerning an effect / outcome implicitly provides support for the referenced step, providing >~1%, >~5%, >~10%, >~20%, >~25%, >~33%, >~50%, >~51%, >~66%, >~75%, >~90%, >~95%, >~99%, or -100% of the effect / outcome, representing >~1%, >~5%, >~10%, >~20%, >~25%, >~33%, >~50%, >~51%, >~66%, >~75%, >~90%, >~95%, >~99%, or -100% of the steps / effortperformed, or both. Explicit listing of percentages of elements in connection with particular aspects does not limit or contradict such implicit disclosure. Uncontradicted, readers should interpret terms such as “essentially all” or “essentially” consistent with the concept of “consisting essentially of.”

[0041] Uncontradicted, terms such as “comprising” when used in connection with a step of a method provide implicit support for performing the step once, > 2 times, or until an associated function / effect is achieved.

[0042] Further, readers will understand that uncontradicted, use of terms such as “comprising” or “including” provides aspects for which the referenced element (or step(s), etc.) is “generally” present, “substantially” present, “essentially” present, or is preset. In certain alternative aspects, “comprising” or “including” can refer to something that is mostly present, about equally present, or is present in another amount, such as about 40%, about 50%, etc. In certain aspects, accordingly, the use of “comprising” and “including” provides support for referenced element(s) to be present in “significant” amounts (e.g., a statistically significant amount) or in DOS amounts, in “some” amount, or, e.g., a “predominate” amount.

[0043] Uncontradicted, any disclosure of an object or method (e.g., composition, device, or system) “comprising” or “including” element(s) provides implicit support for an alternative corresponding aspect that is characterized by the object consisting of that element or “consisting essentially of’ that element (excluding anything that would “materially affect” the “basic and novel characteristic(s)” of any inventive aspect of this disclosure). Uncontradicted, any specific use of phrases such as “consists of’ and “consists essentially of’ herein does not modify this construction principle.

[0044] Readers will understand the “basic and novel characteristic(s)” of an invention provided in this disclosure and the scope of what constitutes a “material effect” (or “material effect”) of such “basic and novel characteristics” will vary with the specific applicable aspect at issue. Uncontradicted, the basic and novel characteristics of any inventive aspect include the specific recited and associated elements of an aspect and exclude any other element that significantly detracts from the intended function(s) of the recited elements, that introduce significant new functions that are unrelated to the intended function(s), that significantly reduce the performance of the function(s), or that significantly negatively change other characteristics of performing such function(s) (e.g., by increasing the cost of performing the functions in energy, money, or both). Uncontradicted, the basic and novel characteristics also include at least significantly retaining the suitability, effectiveness, or both, of recited elements or theoverall aspect. Accordingly, a material effect can be an effect that reduces, diminishes, eliminates, counteracts, cancels, or prevents one or more of such functions in one or more respects (e.g., delaying onset, reducing scope, reducing duration, reducing output, reducing the level of applicability, reducing effect, or combinations thereof). In an aspect, a material effect is one that changes such functions by making such functions impractical, difficult to obtain, or materially more expensive or otherwise costly in terms of inputs. From this and the other guidance provided herein, readers can understand the scope of an aspect that is defined by consisting essentially of a collection of elements.

[0045] Uncontradicted, the term “one” means a single type, single iteration / copy / thing, of a recited element or step, or both, which will be clear from the context of the relevant disclosure. For example, the referent “one” used with respect to a component of a composition / article or system can refer to one type of element (which may be present in numerous copies, as in the case of an ingredient in a composition) one unit of the element, or both. Similarly, “one” component, a “single” component, or the “only component” of a system typically means 1 type of element (which may be present in numerous copies), 1 instance / unit of the element, or both. Further, “one” step of a method typically means performing one type of action (step), one iteration of a step, or both. Uncontradicted, a disclosure of “one” element provides support for both, but uncontradicted, any claim to any “one” element means one type of such an element (e.g., a type of component of a composition / system / article).

[0046] Uncontradicted, the term “some” means > 2 copies / instances or > 5% (e.g., >7.5%, >12.5%, >17.5%, >27.5%, or >37.5%) of a listed collection / whole is or is made up of an element. Regarding methods, some means >5% of an effect, effort, or both is made up of or is attributable to a step (e.g., as in “some of the method is performed by step Y”) or indicates a step is performed >2 times (e.g., as in “step X is repeated some number of times”). Terms such as “considerable amount” or “considerable portion” mean at least 1%, 2%, or 2.5%, but less than most of a whole, such as 2.5-25%, e.g., 5-25%, 5-20%, 7.5-22.5%, 10-20%, 2.5-10%, 2.5- 12.5%, 5-15%, etc. Terms such as “sizable portion” mean 10-50% and in aspects 15-50%, 20- 50%, or 25-50%, or subranges thereof (e.g., 15-45%, 20-40%, 25-45%, etc.). Terms such as “predominately,” “most,” or “mostly” (and “primarily” when not used to refer to an order of events or “mainly”) means detectably >50% (e.g., mostly comprises, predominately includes, etc., mean >50%) (e.g., a system that mostly includes element X is composed of >50% of element X). The term “generally” means >75% (e.g., generally consists of, generally associated with, generally comprises, etc., means >75%) (e.g., a method that generally consists of step Xmeans that 75% of the effort or effect of the method is attributable to step X). “Substantially” or “nearly” means >95% (e.g., nearly all, substantially consists of, etc., mean >95%) (e.g., a collection that nearly entirely is made up of element X means that at least 95% of the elements in the collection are element X). Terms such as “generally free” of an element or “generally lacking” an element mean comprising <25~% of an element, and terms such as “substantially free” of an element mean comprising <~5% of an element. Uncontradicted, any aspect described as “generally comprising” or “generally consisting” of an element implicitly discloses an element that “substantially comprises” the element. The same principle applies to any disclosure where an aspect is described as being “generally free” of an element.

[0047] Uncontradicted, phrases such as “substantially identical” or “substantially similar” may be used to refer to element(s) / component(s) / ingredient(s) / thing(s) (e.g., composition, system, device, etc.) or step(s) / method(s) that have the same or about the same characteristic(s) or achieve the same or about the same result(s), typically in a similar way, as a referenced element / thing or step / method or otherwise do not meaningfully differ in intended result and manner of achieving such a result or are otherwise recognized in the art as not differing or not differing substantially in the relevant context (e.g., by being considered equivalents). Uncontradicted, readers will understand that a “substantially identical” or “substantially similar” element / thing or step / method when compared to a comparator thing / element or method / step means that the referenced element / thing or step / method exhibits such a similar function as a comparator at identical, approximately identical, or statistically similar amounts as the comparator thing or method when applied under similar conditions of use. Again, where statistical, approximate, or other measured comparisons are not possible, readers will understand the phrase as encompassing those things known as being identical or substantially identical to the referenced element / step or are described as such herein.

[0048] Uncontradicted, any aspect described concerning an optionally present element(s) / step(s) also provides implicit support for corresponding aspect(s) in which one, some, most, generally all, nearly all, essentially all, or all such element(s) are lacking / step(s) not performed, in respect of the relevant aspect. E.g., disclosure of a system comprising element X implicitly also supports a system lacking element X. That is, readers will understand that any element, feature, step, or characteristic of any aspect of the technology recited herein as being present in an aspect also implicitly provides support for the element, feature, step, or characteristic as being excluded from a corresponding / similar aspect implicitly disclosed by the explicit positive disclosure and vice versa. Uncontradicted, changes to tense or presentation ofterms (e.g., using “comprises predominately” in place of “predominately comprises”) do not change the meaning of the corresponding term / phrase.

[0049] Uncontradicted, all methods provided here can be performed in any suitable order regardless of presentation (e.g., a method comprising steps A, B, and C can be performed in the order C, B, and A; B and A and C simultaneously, etc.). Uncontradicted, elements of a composition can be assembled in any suitable manner by any suitable method. In general, any methods and materials similar or equivalent to those described here can be used in the practice of embodiments in at least the broadest version of the relevant aspect. Uncontradicted, the use of ordinal numbers such as “first,” “second,” “third,” and so on is primarily, though not exclusively, intended to distinguish respective elements rather than to limit the disclosure to a particular order of those elements, importance, or configuration.

[0050] Any elements associated with a function can be alternatively described as “means for" performing a function in a composition / device / system or a “step for” performing a part of a method, and parts of this disclosure refer to “equivalents," which means known equivalents known in the art for achieving a referenced function associated with disclosed mean(s) / step(s). However, no element of this disclosure or claim should be interpreted as limited to a “means- plus-function” or “step-plus-function” construction unless such intent is clearly indicated by the use of the terms “means for" or “step for.” Terms such as “configured to” or “adapted to” do not indicate “means-plus-function” interpretation but, rather, describe element(s) / step(s) configured to, designed to, selected to, or adapted to achieve a certain performance, characteristic, property, or the like using teachings provided here or in the art.

[0051] As used herein, the word “exemplary” means “serving as an example, instance, or illustration.” Any embodiment described herein as “exemplary,” “representative,” or “illustrative,” etc., should not necessarily be construed as preferred or advantageous over other embodiments. Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0052] Except where explicitly indicated or clearly indicated by context, terms such as “improved” or “better” mean DOS increased (e.g., sizably, constrained sizably, majorly, or significantly increased, etc.). In some respects, as will be clear from context or knowledge, terms such as “improved” or “better” mean DOS “reduced,” such as concerning reducing negative elements of a method or composition. Uncontradicted, terms such as “enhanced,” “improved,” “better,” and the like are used synonymously.

[0053] Any reference to a trademark name (product trademark (™)) incorporates all publicly known information about that product as of the filing date of this Application. Further, reference to a trademarked name is intended to refer to those product(s) as recognizable to PHOSITA as of the date of filing of this Application but also to product(s) that are similar to such product(s), such as product(s) demonstrating biosimilarity; are biologically the same; are functionally the same (perform the same function(s)); are operationally the same (operate on the same key principles or by way of the same feature(s)); comprise the same key characteristic(s), component s), mechanism(s), etc. PHOSITA should recognize, however, that simplified and alternative product(s) from those provided herein could be provided; e.g., modification(s) of the product(s) described herein which maintain the spirit of this disclosure are incorporated.

[0054] Regarding figures, graphs, and the like disclosed in this Application, such figures, graphs, and the like are exemplary and their disclosure concurrently provides disclosure of anything statistically significantly close to or which is “about” the same as the disclosure - e.g., as the data, feature(s) / characteristic(s), and demonstrated performance characteristic(s) provided. For example, any / all data points provided in, e.g., graph(s) disclosed in this Application incorporate data point(s) within a range of statistical similarity and points which are about the same (e.g., within a reasonable fraction of an order of magnitude) as those exemplified. Graph(s) or figure(s) provided herein should be understood to include, where such feature(s) are present, data providing similar patterns, shapes, curves, peaks, etc.

[0055] All references (e.g., publications, patent applications, and patents) cited herein are hereby incorporated by reference as if each reference were individually and specifically indicated to be incorporated by reference and set forth in its entirety herein. Uncontradicted, any suitable principles, methods, or elements of such references (collectively “teachings”) can be combined with or adapted to aspects. However, citation / incorporation of patent documents is limited to the technical disclosure thereof and does not reflect any view regarding the validity, patentability, etc., thereof. Uncontradicted, in the event of any conflict between this disclosure and the teachings of such documents, the content of this disclosure takes precedence regarding interpreting aspects of the disclosure. Numerous references are cited here to concisely incorporate known information and aid skilled persons in putting aspects into practice. While efforts have been made to include the most relevant references for such purposes, readers will understand that not every aspect of every cited reference will apply to every aspect of this disclosure or the technology.

[0056] While elements disclosed in such incorporated references can be combined with aspects of the disclosure provided herein, readers will understand that the described technology is intended to stand apart from such disclosures and, accordingly, uncontradicted, in aspects, any element(s) of the objects or methods of any such references can be considered to be excluded from the scope of what is presented as new technology here (e.g., if reference A discloses object or element B, any aspect that is not directed to object or element B can be characterized by, as one aspect, the lack of object or element B).

[0057] All original claims contained in this disclosure, when filed, are incorporated into this specification as if they were a part of the description.Additional Terms, Concepts, and Acronyms

[0058] The following description of certain terms and acronyms is provided to assist readers in understanding the invention. Additional acronyms may be only provided in other parts of this disclosure and acronyms that are well known in the art may not be provided here.

[0059] Uncontradicted, any description of weight is weight percent (percent by weight) ("wt.%").

[0060] In aspects, "improved" herein means "increased." In aspects, "improved" means "reduced," such as with respect to, e.g., fasting glucose levels or, e.g., levels of hemoglobin Ale. Uncontradicted, terms such as "enhanced," "improved," and the like are used synonymously.

[0061] "Pharmaceutical suitability" and "pharmaceutically suitable" are phrases typically used to refer to compositions / formulations that are safe and effective for pharmaceutical administration and application, having sufficient potency, purity, strength, quality, and safety for pharmaceutical application, as may be judged by regulatory authority review, and as established by, e.g., one or more well controlled and adequate clinical studies performed in compliance with generally prevailing regulatory authority standards.

[0062] Steps, elements, devices, components, and the like also or alternatively can be described as “effective.” Uncontradicted, any step performed, function of a component, etc., is to be understood as being applied effectively, such as in an effective amount, which generally means, in this context, an amount that is effective for the described function(s) associated with the component, device, step, etc. Efficacy in this respect can mean, and, uncontradicted, should be interpreted to implicitly disclose efficacy in terms of (1) in a treated subject, (2) in a majority of subjects in a population, (3) in a statistically significant number of subjects in a population,(4) generally all subjects in a population, (5) substantially all subjects in a population, or (6) in a statistically significant number of or more of a typical or average subject of the class of subjects to be treated in the condition (treatment in this sense encompassing any administration, application, etc., whether for therapeutic reasons or prophylactic / maintenance reasons).

[0063] Excipients and other elements of compositions described herein are typically present in "effective amounts," and uncontradicted, any described class of excipient or specific excipient or other type of element / component of a composition is understood to be present in the associated composition / formulation in an effective amount, which generally means, in this context, an amount that is effective for the described function(s) associated with the excipient (it being understood that some excipient compound(s) / ingredient(s) exhibit more than one effect). E.g., a tonicity agent will be understood to be present in a composition / formulation in an amount that is effective to impart an indicated tonicity effect, a tonicity effect that is required for suitability of the composition, or an effect that imparts a significant tonicity effect on a composition (with respect to a comparator composition lacking the compound(s) / ingredient(s)).

[0064] Readers should note that some terms specific to the field or that are specific to this disclosure also or alternatively are provided in the Summary / Detailed Description sections or elsewhere. Uncontradicted, any repetition of term description is meant to reflect alternative aspects that are characterized by the different meanings or examples of such terms.SUMMARY OF THE INVENTION

[0065] The embodiment s) of the invention described and claimed herein have many attributes and aspects including, but not limited to, those set forth in, e.g., described or referenced in, this Summary. This Summary of the Invention ("Summary") is not intended to be all-inclusive, and the scope of the invention is not limited to or by the aspects, features, elements, or embodiments provided in this Summary, which is included for illustrative purposes only and not restriction. Any of the aspects described under this section can be combined with any other aspect described in this section or with any other aspect of this disclosure.

[0066] In aspects, the invention provides long-acting microparticulate composition(s) and formulation(s) for use in the treatment of diabetes, obesity, or both. In aspects, the long- acting composition(s) and formulation(s) provided herein provide suitable release of the active ingredient over an extended period of time such as at least about 1 month.

[0067] In aspects, the invention provides long-acting, injectable compositions of microparticles wherein the microparticle(s) comprise one or more active pharmaceuticalingredient(s) (API(s)) and a carrier. In aspect(s), the one or more API(s) is selected from one or more melanocortin receptor agonist which is an agonist at one or more of melanocortin-1 receptor (MCI), melanocortin-2 receptor (MC2), melanocortin-3 receptor (MC3), melanocortin-4 receptor (MC4), and melanocortin-5 receptor (MC5) and incretin hormone agonist which is an agonist at one or more of glucagon-like peptide-1 (GLP-1), glucosedependent insulin-tropic polypeptide (GIP), and glucagon receptor, and combination thereof. In aspects, the microparticle composition(s) comprise microparticles each comprising the same one or more API(s). In aspects, the microparticle composition(s) comprise a mixture of microparticles wherein the mixture contains at least two sub-populations of microparticles, each sub-population comprising microparticles comprising different API(s) than that of a different sub-population.

[0068] In aspects, the invention provides long-acting, injectable formulation(s) comprising a composition of microparticles comprising one or more active pharmaceutical ingredient(s) or a pharmaceutically acceptable salt thereof which is an agonist at one or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors or which is an agonist at one or more of glucagon-like peptide-1 (GLP-1); glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor, or any combination of any or all thereof, and a carrier. In aspects, formulations comprise a microparticulate composition comprising the API(s) and a carrier, wherein the prolonged release of API therefrom allows for a frequency of administration of no more than once per month. In certain aspects, the longevity of action of a single dose of formulation(s) provided herein detectably or significantly increases compliance compared to similar composition(s) or formulation(s) requiring more frequent administration, e.g., requiring once-per-week administration. In certain aspects, the longevity of action of a single dose of formulation(s) provided herein detectably or significantly decreases one or more side effects related to the injection of composition(s) or formulation(s), one or more side effects related to the API(s) of such composition(s) or formulation(s), or a combination of any or all thereof compared to similar composition(s) or formulation(s) requiring more frequent administration, e.g., requiring once-per-week administration.

[0069] In aspects, the invention provides the microparticulate compositions and formulation(s) comprising such composition(s) described in this section, wherein the microparticles demonstrate remarkably consistent size, shape, and maximum packing density characteristics. In aspects, provided herein are composition(s) of microparticles andformulation(s) made therefrom wherein the composition(s) and formulation(s) comprise an amount of any API which is unattached to, unencapsulated by, unincorporated by, or otherwise unassociated with a carrier material (such that it is characterizable as “free” API) which is sufficiently low so as to provide a controlled release of API upon administration over the course of an administration without demonstrating a detectable or significant burst effect. In certain aspects, microparticulate composition(s) are established using double-emulsion technology to yield peptide-loaded, monodisperse microspheres with limited porosity. In aspects, steps associated with double-emulsion technology method(s) described herein comprise a suitable washing step to leave less than about 5%, <4%, <3%, <2%, <1%, <0.05%, <0.01%, or even less, of API, or any amount of API capable of producing a burst effect upon administration of formulation(s) comprising the microparticulate composition(s). In aspects, the controlled release composition(s) (e.g., the formulation(s) comprising such composition(s)) described herein can be administered once per month or even less frequently, e.g., once every 3, 6, 9, or 12 months.

[0070] According to certain embodiments, the invention herein provides pharmaceutically acceptable, controlled-release microparticle composition(s) and formulation(s) comprising such composition(s) for use in the treatment of obesity, diabetes, or both, wherein composition(s) and formulation(s) comprise microparticles comprising API(s) and biodegradable polymer compound(s). and obese patient of composition(s) and formulation(s) herein can, in certain respects, demonstrate detectable or significant agonist activity against one or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors , or glucagon-like peptide- 1 (GLP- 1); glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor and typically have a molecular weight of at least about 1000 Da.EXEMPLARY ASPECTS OF THE INVENTION

[0071] The following is a non-limiting list of exemplary aspects of the invention, which illustrates embodiments of the invention in a summary form to aid readers in quickly understanding the overall scope of the invention. Similar to patent claims, listed aspects described in the paragraphs of this section may make reference to (depend on / from) one or more other paragraphs. Readers will understand that such references mean that the features / characteristics or steps of such referenced aspects are incorporated into / combined with the referring aspect. E.g., if an aspect in a paragraph (e.g., a paragraph indicated by text at the end of the paragraph as aspect 2) refers to another aspect by one or more aspect numbers (e.g.,aspect 1 or "any one of aspects 1-3"), it will be understood to include the elements, steps, or characteristics of such referenced aspects (e.g., aspect 1) in addition to those of the aspect in which the reference is made (e.g., if aspect 2 refers to aspect 1, it provides a description of a composition, method, system, device, etc., including the features of both aspect 1 and aspect 2).

[0072] Lists of aspects describing specific exemplary embodiments of the invention are sometimes employed for aiding the reader in understanding the invention. Such aspects can, within them, reference other exemplary aspects, either individually or as groups of aspects (e.g., via reference to a range within a list of numbered aspects when such aspects are provided as a numbered list). Reference to ranges of aspects should be interpreted as referencing all such aspects individually, each as unique embodiments of the invention, and in combination with one another as unique embodiment(s) of the invention, according to the presentation provided of such aspects unless such an aspect within such a referenced range is either contradictory or nonsensical. If contradicted, reference to the contradictory aspect should be excluded.COMPOSITION(S)

[0073] In a first aspect, the invention provides a pharmaceutically acceptable, controlled release, pharmaceutically acceptable composition comprising a population of microparticles, the microparticles of the population of microparticles comprising (1) one or more active pharmaceutical ingredient(s) or a pharmaceutically acceptable salt thereof which is an agonist at one or more of melanocortin-1 (MCI); melanocortin-2 (MC2); melanocortin-3 (MC3); melanocortin-4 (MC4); or melanocortin-5 (MC5) receptors or which is an agonist at one or more of glucagon-like peptide- 1 (GLP-1); glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor or combination of thereof and (2) a carrier component comprising one or more biodegradable polymers, wherein the maximum dimension in any one direction of the microparticles in the composition is between about 1 pm and about 120 pm; at least about 70% of the microparticles in the composition have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the average dimension of the microparticles in any other one or more directions within the same microparticle. (ASPECT 1.)

[0074] In one aspect, the invention provides a pharmaceutically acceptable, controlled release, pharmaceutically acceptable composition comprising a population of microparticles, the microparticles of the population of microparticles comprising (1) one or more activepharmaceutical ingredients (API)(s) is selected from retatrutide, tirzepatide, setmelanotide, lixisenatide, dulaglutide, liraglutide, albiglutide, and pemvidutide, and (2) a carrier component comprising one or more biodegradable polymers, wherein the maximum dimension in any one direction of the microparticles in the composition is between about 1 pm and about 120 pm; at least about 70% of the microparticles in the composition have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the average dimension of the microparticles in any other one or more direction(s) within the same microparticle. (ASPECT 2.)

[0075] In one aspect, the invention provides a pharmaceutically acceptable, controlled release, pharmaceutically acceptable composition comprising a population of microparticles, the microparticles of the population of microparticles comprising (1) one or more active pharmaceutical ingredient(s) (API)(s) is selected from retatrutide, tirzepatide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide, and (2) a carrier component comprising one or more biodegradable polymers, wherein the maximum dimension in any one direction of the microparticles in the composition is between about 1 pm and about 120 pm; at least about 70% of the microparticles in the composition have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the average dimension of the microparticles in any other one or more directi on(s) within the same microparticle. (ASPECT 3.)

[0076] In one aspect, the invention provides a pharmaceutically acceptable, controlled release, pharmaceutically acceptable composition comprising a population of microparticles, the microparticles of the population of microparticles comprising (1) one or more active pharmaceutical ingredient s (API)(s) is component selected from retatrutide, tirzepatide, setmelanotide, lixisenatide, dulaglutide, liraglutide, albiglutide, and pemvidutide, and (2) a carrier component comprising one or more biodegradable polymers, wherein the maximum dimension in any one direction of the microparticles in the composition is between about 1 pm and about 120 pm; at least about 70% of the microparticles in the composition have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the averagedimension of the microparticles in any other one or more direction(s) within the same microparticle. (ASPECT 4.)

[0077] In certain aspects, the invention provides the composition of any one or more of aspects 1 - 4, wherein the composition is suitable for parenteral administration. (ASPECT 5.)

[0078] In certain aspects, the invention provides the composition of aspect 5, wherein the composition is administered by subcutaneous injection. (ASPECT 6.)

[0079] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises retatrutide. (ASPECT 7.)

[0080] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises tirzepatide. (ASPECT 8.)

[0081] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises setmelanotide. (ASPECT 9.)

[0082] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises pemvidutide. (ASPECT 10.)

[0083] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises lixisenatide. (ASPECT 11.)

[0084] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises dulaglutide. (ASPECT 12.)

[0085] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises liraglutide. (ASPECT 13.)

[0086] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API comprises albiglutide. (ASPECT 14.)

[0087] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API is selected from a group comprising retatrutide, tirzepatide, setmelanotide, and pemvidutide, and combination thereof. (ASPECT 15)

[0088] In aspects, the invention provides the composition of any one or more of aspects 1 - 6, wherein the API is selected from a group comprising lixisenatide, dulaglutide, liraglutide, albiglutide, retatrutide, pemvidutide, and tirzepatide, and combination thereof. (ASPECT 16)

[0089] In aspects, the invention provides the composition of any one or more of aspects 1 - 16, wherein the API of the composition is present in an amount representing between about 1 wt.% and about 40 wt.% of the microparticle. (ASPECT 17.)

[0090] In aspects, the invention provides the composition of any one or more of aspects 1 - 16, wherein the API of the composition is present in an amount representing between about 4 wt.% and about 40 wt.% of the microparticle. (ASPECT 18.)

[0091] In aspects, the invention provides the composition of any one or more of aspects 1 - 16, wherein the API of the composition is present in an amount representing between about 10 wt.% and about 25 wt.% of the microparticle. (ASPECT 19.)

[0092] In aspects, the invention provides the composition of any one or more of aspects 1 - 16, wherein the API of the composition is present in an amount representing between about 4 wt.% and about 15 wt.% of the microparticle. (ASPECT 20.)

[0093] In aspects, the invention provides the composition of any one or more of aspects 1 - 20, wherein the composition is provided as a suspension formulation, and wherein the API is present in the suspension formulation in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 21.)

[0094] In aspects, the invention provides the composition of aspect 21, wherein the API is present in the suspension formulation in an amount representing between about 0.1 wt.% and about 3 wt.% of the suspension. (ASPECT 22.)

[0095] In aspects, the invention provides the composition of aspect 21, wherein the API is present in the suspension formulation in an amount representing between about 3 wt.% and about 10 wt.% of the suspension (ASPECT 23.)

[0096] In aspects, the invention provides the composition of any one or more of aspects 1 - 23, wherein each dose of the composition provides an amount of a single API or the API component of between about 1 mg and about 300 mg. (ASPECT 24.)

[0097] In aspects, the invention provides the composition of any one or more of aspects 1 - 24, wherein at least one of the one or more biodegradable polymers of the carrier component comprises PLGA. (ASPECT 25.)

[0098] In aspects, the invention provides the composition of any one or more of aspects 1 - 25, wherein at least one of the one or more biodegradable polymers of the carrier component comprises PLA. (ASPECT 26.)

[0099] In aspects, the invention provides the composition of aspect 25, wherein the only biodegradable polymer of the carrier component is PLGA. (ASPECT 27.)

[0100] In aspects, the invention provides the composition of aspect 26, wherein the only biodegradable polymer of the carrier component is PLA. (ASPECT 28.)

[0101] In aspects, the invention provides the composition of any one or both of aspect 25 and aspect 27, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid: glycolic acid) is about 70 - 85 : about 15 - 30. (ASPECT 29.)

[0102] In aspects, the invention provides the composition of any one or both of aspect 22 and aspect 27, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid: glycolic acid) is about 70 - 80 : about 20 - 30. (ASPECT 30.)

[0103] In aspects, the invention provides the composition of any one or both of aspect 25 and aspect 27, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid: glycolic acid) is about 60 - 80 to about 20 -40. (ASPECT 31.)

[0104] In aspects, the invention provides the composition of any one or both of aspect 25 and aspect 27, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid: glycolic acid) is about 50 : about 50. (ASPECT 32.)

[0105] In aspects, the invention provides the composition of any one or both of aspect 25 and aspect 27, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid: glycolic acid) is about 75 : about 25. (ASPECT 33.)

[0106] In aspects, the invention provides the composition of any one or more of aspects 1 - 33, wherein the composition is provided as a lyophilized powder ready for reconstitution prior to administration. (ASPECT 34.)

[0107] In aspects, the invention provides the composition of any one or more of aspects 1 - 33, wherein the composition is provided as an injectable gel. (ASPECT 35.)

[0108] In aspects, the invention provides the composition of any one or more of aspects 1 - 33, wherein the composition is provided as a suspension having a suspension density of microparticles of between about 1% and about 50%, and wherein the API component is present in the suspension in an amount of between about 0.4 mg / mL and about 120 mg / mL. (ASPECT 36.)

[0109] In aspects, the invention provides the composition of any one or more of aspects 1 - 33, wherein the composition is provided as a suspension, and wherein the suspension further comprises one or more of a surfactant component, a suspension component, an osmolality component, a buffer component, and a vehicle component. (ASPECT 37.)

[0110] In aspects, the invention provides the composition of aspect 37, wherein the suspension comprises a surfactant component. (ASPECT 38.)[OHl] In aspects, the invention provides the composition of any one or both of aspect 37 and aspect 38, wherein the suspension comprises a surfactant component present in thesuspension in an amount representing between about 0.01 wt.% and about 10 wt.% of the suspension. (ASPECT 39.)

[0112] In aspects, the invention provides the composition of any one or both of aspect 37 and aspect 38, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.05 wt.% and about 10 wt.% of the suspension. (ASPECT 40.)

[0113] In aspects, the invention provides the composition of any one or more of aspects 37 - 40, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.1 wt.% and about 5 wt.% of the suspension. (ASPECT41.)

[0114] In aspects, the invention provides the composition of any one or more of aspects 37 - 40, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT42.)

[0115] In aspects, the invention provides the composition of any one or more of aspects 37 - 42, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.01 wt.% and about 0.10 wt.% of the suspension. (ASPECT 43)

[0116] In aspects, the invention provides the composition of any one or more of aspects 37 - 43, wherein the suspension comprises a surfactant component comprising polysorbate 20, polysorbate 80, polyvinyl alcohol, or a combination of any or all thereof. (ASPECT 44.)

[0117] In aspects, the invention provides the composition of any one or more of aspects 37 - 44, wherein the suspension comprises a suspension component. (ASPECT 45.)

[0118] In aspects, the invention provides the composition of any one more of aspects 37- 45, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.05 wt.% and about 15 wt.% of the suspension. (ASPECT46.)

[0119] In aspects, the invention provides the composition of any one or more of aspects 37 - 46, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT47.)

[0120] In aspects, the invention provides the composition of any one more of aspects 37- 47, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 1 wt.% and about 15 wt.% of the suspension. (ASPECT 48.)

[0121] In aspects, the invention provides the composition of any one more of aspects 37- 48, wherein the suspension comprises a suspension component polyethylene glycol present in the suspension in an amount representing between about 0.1 wt.% and about 15 wt.% of the suspension (ASPECT 49.)

[0122] In aspects, the invention provides the composition of any one more of aspects 37- 49, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 5 wt.% and about 15 wt.% of the suspension. (ASPECT 50.)

[0123] In aspects, the invention provides the composition of any one or more of aspects 37 - 50, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 51.)

[0124] In aspects, the invention provides the composition of any one or more of aspects 37 - 51, wherein the suspension comprises a suspension component comprising polyethylene glycol, carboxymethylcellulose, or a combination thereof. (ASPECT 52.)

[0125] In aspects, the invention provides the composition of any one or more of aspects 37 - 52, wherein the suspension comprises one or more tonicity / osmolality components.(ASPECT 53.)

[0126] In aspects, the invention provides the composition of any one more of aspects 37- 53, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.005 wt.% and about 10 wt.% of the suspension. (ASPECT 54.)

[0127] In aspects, the invention provides the composition of any one more of aspects 37- 54, wherein the suspension comprises tonicity / osmolality component sodium chloride present in the suspension in an amount representing between about 0.1 wt.% and about 1.0 wt.% of the suspension. (ASPECT 55.)

[0128] In aspects, the invention provides the composition of any one more of aspects 37- 55, wherein the suspension comprises tonicity / osmolality component potassium chloride present in the suspension in an amount representing between about 0.005 wt.% and about 0.015 wt.% of the suspension. (ASPECT 56.)

[0129] In aspects, the invention provides the composition of any one more of aspects 37- 56, wherein the suspension comprises tonicity / osmolality components sodium chloride and potassium chloride present in the suspension in an amount representing between about 0.005 wt.% and about 1.0 wt.% of the suspension. (ASPECT 57.)

[0130] In aspects, the invention provides the composition of any one more of aspects 37- 57, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.05 wt.% and about 10 wt.% of the suspension. (ASPECT 58.)

[0131] In aspects, the invention provides the composition of any one more of aspects 37- 58, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 59.)

[0132] In aspects, the invention provides the composition of any one more of aspects 37- 59, wherein the suspension comprises tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 1.0 wt.% of the suspension. (ASPECT 60.)

[0133] In aspects, the invention provides the composition of any one or more of aspects 37 - 60, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.1 wt.% and about 5 wt.% of the suspension. (ASPECT 61.)

[0134] In aspects, the invention provides the composition of any one or more of aspects 37 - 61, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 62.)

[0135] In aspects, the invention provides the composition of any one more of aspects 37- 62, wherein the suspension comprises a tonicity / osmolality component present in the suspension in an amount representing between about 0.005 wt.% and about 0.015 wt.% of the suspension. (ASPECT 63.)

[0136] In aspects, the invention provides the composition of any one or more of aspects 37 - 63, wherein the suspension comprises a tonicity / osmolality component comprising sodium chloride, potassium chloride, mannitol, or a combination thereof. (ASPECT 64.)

[0137] In aspects, the invention provides the composition of any one or more of aspects 37 - 64, wherein the suspension comprises a buffer component. (ASPECT 65.)

[0138] In aspects, the invention provides the composition of any one more of aspects 37- 65, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.005 wt.% and about 10 wt.% of the suspension. (ASPECT66.)

[0139] In aspects, the invention provides the composition of any one more of aspects 37- 66, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.01 wt.% and about 10 wt.% of the suspension. (ASPECT67.)

[0140] In aspects, the invention provides the composition of any one or more of aspects 37 - 67, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.05 wt.% and about 5 wt.% of the suspension. (ASPECT68.)

[0141] In aspects, the invention provides the composition of any one or more of aspects 37 - 68, wherein the suspension comprises one or more tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 69.)

[0142] In aspects, the invention provides the composition of any one or more of aspects 37 - 69, wherein the suspension comprises a tonicity / osmolality component present in the suspension in an amount representing between about 0.005 wt.% and about 0.015 wt.% of the suspension. (ASPECT 70.)

[0143] In aspects, the invention provides the composition of any one or more of aspects 37 - 70, wherein the suspension comprises a buffer component comprising sodium dihydrogen phosphate monohydrate and citric acid or disodium hydrogen phosphate and sodium hydroxide. (ASPECT 71.)

[0144] In aspects, the invention provides the composition of any one or more of aspects 37 - 71, wherein the suspension comprises a buffer component comprising dipotassium phosphate and sodium phosphate dibasic. (ASPECT 72.)

[0145] In aspects, the invention provides the composition of any one or more of aspects 37 - 72, wherein the suspension comprises a vehicle component. (ASPECT 73.)

[0146] In aspects, the invention provides the composition of any one more of aspects 37- 73, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 15 wt.% and about 99 wt.% of the suspension. (ASPECT 74.)

[0147] In aspects, the invention provides the composition of any one more of aspects 37- 74, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 35 wt.% and about 99 wt.% of the suspension. (ASPECT75.)

[0148] In aspects, the invention provides the composition of any one or more of aspects 37 - 75, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 60 wt.% and about 80 wt.% of the suspension. (ASPECT76.)

[0149] In aspects, the invention provides the composition of any one or more of aspects 37 - 76, wherein the suspension comprises a vehicle component comprising water for injection (WFI). (ASPECT 77.)

[0150] In aspects, the invention provides the composition of any one or more of aspects1 - 77, wherein Tirzepatide API of the composition is present in an amount representing between about 1 wt.% and about 40 wt.% of the microparticle. (ASPECT 78.)

[0151] In aspects, the invention provides the composition of any one or more of aspects1 - 78, wherein Tirzepatide API of the composition is present in an amount representing between about 4 wt.% and about 40 wt.% of the microparticle. (ASPECT 79.)

[0152] In aspects, the invention provides the composition of any one or more of aspects 1 - 79, wherein Tirzepatide API of the composition is present in an amount representing between about 10 wt.% and about 25 wt.% of the microparticle. (ASPECT 80.)

[0153] In aspects, the invention provides the composition of any one or more of aspects 1 - 80, wherein Tirzepatide API of the composition is present in an amount representing between about 4 wt.% and about 15 wt.% of the microparticle. (ASPECT 81.)

[0154] In aspects, the invention provides the composition of any one or more of aspects 1 - 81, wherein the composition is provided as a suspension formulation, and wherein Tirzepatide API is present in the suspension formulation in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 82.)

[0155] In aspects, the invention provides the composition of aspect 82, wherein Tirzepatide API is present in the suspension formulation in an amount representing between about 0.1 wt.% and about 3 wt.% of the suspension. (ASPECT 83.)

[0156] In aspects, the invention provides the composition of aspect 82, wherein Tirzepatide API is present in the suspension formulation in an amount representing between about 3 wt.% and about 10 wt.% of the suspension (ASPECT 84.)

[0157] In aspects, the invention provides the composition of any one or more of aspects 1 - 84, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in phosphate buffer at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 14 days postadministration or post-placement in phosphate buffer at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or postplacement in phosphate buffer at pH 7.4; or a combination of any or all thereof. (ASPECT 85.)

[0158] In aspects, the invention provides the composition of any one or more of aspects 1 - 85, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in HEPES (N-2-hydroxyethylpiperazine-N- 2-ethane sulfonic acid) at pH 7.3 - 7.5, preferably 7.4; less than about 80% of the administered dose of API(s) is released within the first 14 days post-administration or post-placement in HEPES at pH 7.3 - 7.5, preferably 7.4; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or post-placement in HEPES at pH 7.3 - 7.5, preferably 7.4, or a combination of any or all thereof. (ASPECT 86.)

[0159] In aspects, the invention provides the composition of any one or more of aspects 1 - 86, wherein less than about 2% of the administered dose of Tirzepatide is released within the first 24 hours post-administration or post-placement in 50mM Phosphate buffer pH 7.4 + 13.7 mM NaCl + 0.05 %w / v BRIJ35 at temperature (37°C); and cumulative release at onset is <=15%. (ASPECT 87.)

[0160] In aspects, the invention provides the composition of any one or more of aspects 1 - 86, wherein less than about 3% of the administered dose of Tirzepatide is released within the first 24 hours post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 7% of the administered dose of Tirzepatide is released within the first 14 days post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 38% of the administered dose of Tirzepatide is released within the first 30 days post-administration or post- placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 82% of the administered dose of Tirzepatide is released within the first 43 days post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); or a combination of any or all thereof. (ASPECT 88.)

[0161] In aspects, the invention provides the composition of any one or more of aspects 1 - 86, wherein less than about 7% of the administered dose of Tirzepatide is released within thefirst 24 hours post-administration or post-placement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); less than about 65% of the administered dose of Tirzepatide is released within the first 14 days post-administration or post-placement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); less than about 80% of the administered dose of Tirzepatide is released within the first 30 days post-administration or postplacement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); less than about 80% of the administered dose of Tirzepatide is released within the first 43 days postadministration or post-placement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); or a combination of any or all thereof. (ASPECT 89.)

[0162] In aspects, the invention provides the composition of any one or more of aspects 1 - 89, wherein the microparticles release API(s) under physiological conditions at an at least generally controlled, at least substantially controlled, at least essentially controlled, or at a controlled rate, such that the release profile of the composition does not demonstrate a detectable or significant burst effect. (ASPECT 90.)

[0163] In aspects, the invention provides the composition of any one or more of aspects 1 - 90, tirzepatide is released from the composition in a controlled release order selected from zero, first, second and third release order, and any pseudo orders thereof. Each possibility represents a separate embodiment. (ASPECT 91.)FORMULATIONS

[0164] In one aspect, the invention provides a pharmaceutically acceptable, controlled release formulation comprising (1) a composition comprising a population of microparticles, the microparticles of the composition comprising (a) one or more active pharmaceutical ingredient(s) or a pharmaceutically acceptable salt thereof which is an agonist at one or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors or which is an agonist at one or more of glucagon-like peptide- 1 (GLP-1), glucose-dependent insulin-tropic polypeptide (GIP), and glucagon receptor, or a combination of thereof (b) a carrier component comprising one or more biodegradable polymers; and (2) a vehicle component,. (ASPECT 92.)

[0165] In certain aspects, the invention provides the formulation of aspect 92, wherein the formulation is suitable for parenteral administration. (ASPECT 93.)

[0166] In certain aspects, the invention provides the formulation of aspect 93, wherein the formulation is administered by subcutaneous injection. (ASPECT 94.)

[0167] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises retatrutide. (ASPECT 95.)

[0168] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises tirzepatide. (ASPECT 96.)

[0169] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises setmelanotide. (ASPECT 97.)

[0170] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises pemvidutide. (ASPECT 98.)

[0171] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises lixisenatide. (ASPECT 99.)

[0172] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises dulaglutide. (ASPECT 100.)

[0173] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises liraglutide. (ASPECT 101.)

[0174] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation comprises albiglutide. (ASPECT 102.)

[0175] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation is selected from a group comprising retatrutide, tirzepatide, setmelanotide, and pemvidutide, and combination thereof. (ASPECT 103.)

[0176] In aspects, the invention provides the formulation of any one or more of aspects 92 - 94, wherein the API component of the formulation is selected from a group comprising retatrutide, pemvidutide, tirzepatide, setmelanotide, lixisenatide, dulaglutide, liraglutide, and albiglutide, and combination thereof. (ASPECT 104.)

[0177] In aspects, the invention provides the formulation of any one or more of aspects 92 - 104, wherein the API component of microparticles of the formulation is present in an amount representing between about 1 wt.% and about 40 wt.% of the microparticles. (ASPECT 105.)

[0178] In aspects, the invention provides the formulation of aspect 105, wherein the API component of the composition is present in an amount representing between about 4 wt.% and about 40 wt.% of the microparticle. (ASPECT 106.)

[0179] In aspects, the invention provides the formulation of aspect 105, wherein the API component of the formulation is present in an amount representing between about 4 wt.% and about 15 wt.% of the microparticle. (ASPECT 107.)

[0180] In aspects, the invention provides the formulation of aspect 92 - 107, wherein Tirzepatide component is present in an amount between about 10 wt.% and about 25 wt.% of the microparticle. (ASPECT 108.)

[0181] In aspects, the invention provides the formulation of aspect 92 - 108, wherein polymer component is present in an amount between about 75 wt.% and about 90 wt.% of the microparticle. (ASPECT 109.)

[0182] In aspects, the invention provides the formulation of aspect 92 - 109, wherein Tirzepatide component is present in an amount between about 10 wt.% and about 25 wt.%; and polymer component is present in an amount between about 75 wt.% and about 90 wt.% of the microparticle. (ASPECT 110.)

[0183] In aspects, the invention provides the formulation of any one or more of aspects 92 - 110, wherein the formulation is provided as a suspension, and wherein the API component is present in the suspension in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 111.)

[0184] In aspects, the invention provides the formulation of aspect 111, wherein the API component is present in the suspension in an amount representing between about 0.1 wt.% and about 3 wt.% of the suspension. (ASPECT 112.)

[0185] In aspects, the invention provides the formulation of aspect 111, wherein the API component is present in the suspension in an amount representing between about 3 wt.% and about 10 wt.% of the suspension (ASPECT 113.)

[0186] In aspects, the invention provides the formulation of aspect 92-113, wherein the polymer component is present in an amount between about 1 wt.% and about 45 wt.% of the of the suspension. (ASPECT 114.)

[0187] In aspects, the invention provides the formulation of aspect 112-114, wherein the Tirzepatide component is present in an amount of about 3 wt.% and about 10 wt.% and the polymer component is present in an amount between about 15 wt.% and about 35 wt.% of the droplet. (ASPECT 115.)

[0188] In aspects, the invention provides the formulation of any one or more of aspects 92 - 115, wherein each dose of the formulation provides an amount of a single API or the API component of between about 1 mg and about 300 mg. (ASPECT 116.)

[0189] In aspects, the invention provides the formulation of any one or more of aspects 92 - 116, wherein at least one of the one or more biodegradable polymers of the carrier component comprises PLGA. (ASPECT 117.)

[0190] In aspects, the invention provides the formulation of any one or more of aspects 92 - 117, wherein at least one of the one or more biodegradable polymers of the carrier component comprises PLA. (ASPECT 118.)

[0191] In aspects, the invention provides the formulation of aspect 117, wherein the only biodegradable polymer of the carrier component is PLGA. (ASPECT 119.)

[0192] In aspects, the invention provides the formulation of aspect 118, wherein the only biodegradable polymer of the carrier component is PLA. (ASPECT 120.)

[0193] In aspects, the invention provides the formulation of any one or both of aspect117 and aspect 119, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid : glycolic acid) is about 70 - 85 : about 15 - 30. (ASPECT 121.)

[0194] In aspects, the invention provides the formulation of any one or both of aspect118 and aspect 120, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid : glycolic acid) is about 75: about 25. (ASPECT 122.)

[0195] In aspects, the invention provides the formulation of any one or both of aspect 118 and aspect 120, wherein the monomer ratio of lactic acid to glycolic acid (lactic acid : glycolic acid) is about 50: about 50. (ASPECT 123.)

[0196] In aspects, the invention provides the composition of any one or more of aspects 92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 45 degrees. (ASPECT 124.)

[0197] In aspects, the invention provides the composition of any one or more of aspects -92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 40 degrees. (ASPECT 125.)

[0198] In aspects, the invention provides the composition of any one or more of aspects 92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 35 degrees. (ASPECT 126.)

[0199] In aspects, the invention provides the formulation of any one or more of aspects 92 -107 and 78- 84, wherein the formulation is provided as a separate combination of alyophilized microparticle composition and a diluent, wherein the diluent is used to reconstitute the lyophilized microparticle composition prior to administration. (ASPECT 127.)

[0200] In aspects, the invention provides the formulation of any one or more of aspects 92 - 127, wherein the formulation is provided as ready to use suspension or injectable gel. (ASPECT 128.)

[0201] In aspects, the invention provides the formulation of any one or more of aspects 92 - 128, wherein the composition is provided as a suspension having a suspension density of microparticles of between about 1% and about 50%, and wherein the API component is present in the suspension in an amount of between about 0.4 mg / mL and about 120 mg / mL. (ASPECT 129.)

[0202] In aspects, the invention provides the formulation of any one or more of aspects 92 - 129, wherein the composition is provided as a suspension, and wherein the suspension further comprises one or more of a surfactant component, a suspension component, an osmolality component, a buffer component, and a vehicle component. (ASPECT 130.)

[0203] In aspects, the invention provides the formulation of aspect 130, wherein the suspension comprises a surfactant component. (ASPECT 131.)

[0204] In aspects, the invention provides the composition of any one or both of aspect 130 and aspect 131, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.01 wt.% and about 10 wt.% of the suspension. (ASPECT 132.)

[0205] In aspects, the invention provides the formulation of any one or both of aspect 130 and aspect 131, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.05 wt.% and about 10 wt.% of the suspension. (ASPECT 133.)

[0206] In aspects, the invention provides the formulation of any one or more of aspects 130 - 133, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.1 wt.% and about 5 wt.% of the suspension. (ASPECT 134.)

[0207] In aspects, the invention provides the formulation of any one or more of aspects 130 - 134, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 135.)

[0208] In aspects, the invention provides the composition of any one or more of aspects 130 - 135, wherein the suspension comprises a surfactant component present in the suspension in an amount representing between about 0.01 wt.% and about 0.10 wt.% of the suspension. (ASPECT 136.)

[0209] In aspects, the invention provides the formulation of any one or more of aspects 130 - 136, wherein the suspension comprises a surfactant component comprising polysorbate 20, polysorbate 80, polyvinyl alcohol, or a combination of any or all thereof. (ASPECT 137.)

[0210] In aspects, the invention provides the formulation of any one or more of aspects 130 - 137, wherein the suspension comprises a suspension component. (ASPECT 138.)

[0211] In aspects, the invention provides the formulation of any one more of aspects 130 - 138, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.05 wt.% and about 15 wt.% of the suspension. (ASPECT 139.)

[0212] In aspects, the invention provides the formulation of any one or more of aspects 130 - 139, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 140.)

[0213] In aspects, the invention provides the composition of any one more of aspects 130 - 140, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 1 wt.% and about 15 wt.% of the suspension. (ASPECT 141)

[0214] In aspects, the invention provides the composition of any one more of aspects 130 - 141, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 5 wt.% and about 15 wt.% of the suspension.(ASPECT 142)

[0215] In aspects, the invention provides the formulation of any one or more of aspects 130 - 142, wherein the suspension comprises a suspension component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 143.)

[0216] In aspects, the invention provides the formulation of any one or more of aspects 130 - 143, wherein the suspension comprises a suspension component comprising polyethylene glycol, carboxymethylcellulose, or a combination thereof. (ASPECT 144.)

[0217] In aspects, the invention provides the formulation of any one or more of aspects 130 - 144, wherein the suspension comprises one or more tonicity / osmolality component. (ASPECT 145.)

[0218] In aspects, the invention provides the composition of any one more of aspects 130 - 145, wherein the suspension comprises one or more tonicity / osmolality components present in the suspension in an amount representing between about 0.005 wt.% and about 10 wt.% of the suspension. (ASPECT 146)

[0219] In aspects, the invention provides the formulation of any one or more of aspects 130 - 146, wherein the suspension comprises one or more tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 10 wt.% of the suspension. (ASPECT 147.)

[0220] In aspects, the invention provides the formulation of any one more of aspects 130 - 147, wherein the suspension comprises one or more tonicity / osmolality component present in the suspension in an amount representing between about 0.05 wt.% and about 10 wt.% of the suspension. (ASPECT 148.)

[0221] In aspects, the invention provides the formulation of any one or more of aspects 130 - 148, wherein the suspension comprises one or more tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 5 wt.% of the suspension. (ASPECT 149.)

[0222] In aspects, the invention provides the formulation of any one or more of aspects 130 - 149, wherein the suspension comprises a tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 150.)

[0223] In aspects, the invention provides the composition of any one more of aspects 130 - 150, wherein the suspension comprises a tonicity / osmolality component present in the suspension in an amount representing between about 0.005 wt.% and about 0.015 wt.% of the suspension. (ASPECT 151)

[0224] In aspects, the invention provides the formulation of any one or more of aspects 130 - 151, wherein the suspension comprises one or more tonicity / osmolality component comprising sodium chloride, potassium chloride, mannitol, or a combination thereof. (ASPECT 152.)

[0225] In aspects, the invention provides the formulation of any one or more of aspects 130 - 152, wherein the suspension comprises a buffer component. (ASPECT 153.)

[0226] In aspects, the invention provides the composition of any one more of aspects 130 - 153, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.005 wt.% and about 10 wt.% of the suspension. (ASPECT154.)

[0227] In aspects, the invention provides the formulation of any one more of aspects 130 - 154, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.01 wt.% and about 10 wt.% of the suspension. (ASPECT155.)

[0228] In aspects, the invention provides the formulation of any one or more of aspects 130 - 155, wherein the suspension comprises a buffer component present in the suspension in an amount representing between about 0.05 wt.% and about 5 wt.% of the suspension. (ASPECT156.)

[0229] In aspects, the invention provides the formulation of any one or more of aspects 130 - 156, wherein the suspension comprises a tonicity / osmolality component present in the suspension in an amount representing between about 0.1 wt.% and about 1 wt.% of the suspension. (ASPECT 157.)

[0230] In aspects, the invention provides the formulation of any one or more of aspects 130 - 157, wherein the suspension comprises a buffer component comprising sodium dihydrogen phosphate monohydrate and citric acid or disodium hydrogen phosphate and sodium hydroxide and HEPES. (ASPECT 158.)

[0231] In aspects, the invention provides the composition of any one or more of aspects 130 - 158, wherein the suspension comprises a buffer component comprising dipotassium phosphate and sodium phosphate dibasic. (ASPECT 159.)

[0232] In aspects, the invention provides the formulation of any one or more of aspects 130 - 159, wherein the suspension comprises a vehicle component. (ASPECT 160.)

[0233] In aspects, the invention provides the composition of any one more of aspects 130 - 160, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 15 wt.% and about 99 wt.% of the suspension. (ASPECT161.)

[0234] In aspects, the invention provides the formulation of any one more of aspects 130 - 161, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 35 wt.% and about 99 wt.% of the suspension. (ASPECT162.)

[0235] In aspects, the invention provides the formulation of any one or more of aspects 130 - 162, wherein the suspension comprises a vehicle component present in the suspension in an amount representing between about 60 wt.% and about 80 wt.% of the suspension. (ASPECT 163.)

[0236] In aspects, the invention provides the formulation of any one or more of aspects 130 - 163, wherein the suspension comprises a vehicle component comprising water for injection (WFI). (ASPECT 164.)

[0237] In aspects, the invention provides the formulation of any one or more of aspects 130 - 164, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in phosphate buffer at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 14 days postadministration or post-placement in phosphate buffer at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or postplacement in phosphate buffer at pH 7.4; or a combination of any or all thereof. (ASPECT 165).

[0238] In aspects, the invention provides the composition of any one or more of aspects 1 - 86, wherein less than about 2% of the administered dose of Tirzepatide is released within the first 24 hours post-administration or post-placement in 50mM Phosphate buffer pH 7.4 + 13.7 mM NaCl + 0.05 %w / v BRIJ35 at temperature (37°C); and cumulative release at onset is <=15%. (ASPECT 166.)

[0239] In aspects, the invention provides the formulation of any one or more of aspects 130 - 166, wherein less than about 3% of the administered dose of Tirzepatide is released within the first 24 hours post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 7% of the administered dose of Tirzepatide is released within the first 14 days post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 38% of the administered dose of Tirzepatide is released within the first 30 days post-administration or post- placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); less than about 82% of the administered dose of Tirzepatide is released within the first 43 days post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7 at elevated temperature (45°C); or a combination of any or all thereof. (ASPECT 167.)

[0240] In aspects, the invention provides the formulation of any one or more of aspects 130 - 167, wherein less than about 7% of the administered dose of Tirzepatide is released within the first 24 hours post-administration or post-placement in 50 mM borate buffer + 0.05% Brij 35at pH 9 at elevated temperature (45°C); less than about 65% of the administered dose of Tirzepatide is released within the first 14 days post-administration or post-placement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); less than about 80% of the administered dose of Tirzepatide is released within the first 30 days post-administration or postplacement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); less than about 80% of the administered dose of Tirzepatide is released within the first 43 days postadministration or post-placement in 50 mM borate buffer + 0.05% Brij 35 at pH 9 at elevated temperature (45°C); or a combination of any or all thereof. (ASPECT 168.)

[0241] In aspects, the invention provides the formulation of any one or more of aspects 130 - 164, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in HEPES at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 14 days post-administration or postplacement in HEPES at pH 7.4; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or post-placement in HEPES at pH 7.4; or a combination of any or all thereof. (ASPECT 169.)

[0242] In aspects, the invention provides the formulation of any one or more of aspects 130 - 169, wherein the microparticles of the formulation release API(s) under physiological conditions at an at least generally controlled, at least substantially controlled, at least essentially controlled, or at a controlled rate, such that the release profile of the formulation does not demonstrate a detectable or significant burst effect. (ASPECT 170.)PRODUCT BY PROCESS ASPECTS

[0243] In one aspect, the invention provides a pharmaceutically acceptable, controlled release formulation made by a process comprising (1) establishing a population of microparticles, the population of microparticles formed by a process comprising (a) forming a double emulsion comprising (I) a first phase comprising (A) one or more active pharmaceutical ingredient (API) which is an agonist at one or more of melanocortin-1 receptor (MCI); melanocortin-2 receptor (MC2); melanocortin-3 receptor (MC3); melanocortin-4 receptor (MC4); and melanocortin-5 receptor (MC5) or incretin hormone agonist which is an agonist at one or more of glucagon-like peptide-1 (GLP-1) agonist; glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor, or combination of thereof and (B) a first solvent, wherein the first solvent is an aqueous or polar solvent, wherein the first solvent optionally comprises a surfactant component, a buffer component, or both, and wherein the first phaseoptionally comprises an osmolality component; (II) a second phase comprising a carrier component comprising one or more biodegradable polymers and a second solvent, wherein the second solvent is an organic solvent, and wherein the second phase optionally comprises a surfactant; and (III) a third phase comprising (A) a third solvent, wherein the third solvent is an aqueous or polar solvent, wherein the third solvent optionally comprises a buffer component, a bulking component, or both; and (B) a surfactant; (b) performing solvent extraction to remove the second organic solvent; and (c) concentrating the microparticles resulting from steps (a) and (b) and collecting a population of microparticles, wherein (I) the population of microparticles has an maximum dimension in any one direction of between about 10 pm and about 120 pm; (II) at least about 70% of the microparticles in the population of microparticles have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; and (III) at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the average dimension of the microparticle in any other one or more directions within the same microparticle; (2) washing the population of microparticles; and (3) combining the washed microparticle population with a vehicle component,. (ASPECT 171.)

[0244] In aspects, the invention provides the formulation of aspect 171, wherein the first phase does not comprise a surfactant. (ASPECT 172.)

[0245] In aspects, the invention provides the formulation of any one or both of aspect 171 and aspect 172, wherein the second phase does not comprise a surfactant. (ASPECT 173.)

[0246] In aspects, the invention provides the formulation of any one or more of aspects 171 - 173, wherein the second phase does not comprise a tonicity / osmolality component. (ASPECT 174.)

[0247] In aspects, the invention provides the formulation of any one or more of aspects 171 - 174, wherein the formulation has any one or more of the characteristics of formulations in any one or more of aspects 92 - 170. (ASPECT 175.)METHOD(S) OF MANUFACTURE

[0248] In one aspect, the invention provides a method of manufacturing a pharmaceutically acceptable, controlled release composition of microparticles suitable for parenteral administration comprising (1) establishing a population of microparticles by (a) forming a double emulsion comprising (I) a first phase comprising (A) one or more active pharmaceutical ingredient(s) or a pharmaceutically acceptable salt thereof which is an agonist atone or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors or which is an agonist at one or more of glucagon-like peptide- 1 (GLP-1); glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor, or combination of thereof and (B) a first solvent, wherein the first solvent is an aqueous or polar solvent, wherein the first solvent optionally comprises a surfactant component, a buffer component, or both, and wherein the first phase optionally comprise an osmolality component; (II) a second phase comprising a carrier component comprising one or more biodegradable polymers and a second solvent, wherein the second solvent is an organic solvent, and wherein the second phase optionally comprise a surfactant; and (III) a third phase comprising (A) a third solvent, wherein the third solvent is an aqueous or polar solvent, wherein the third solvent optionally comprises a buffer component, a bulking component, or both; and (B) a surfactant; (b) performing solvent extraction to remove the second organic solvent; and (c) concentrating the microparticles resulting from steps (a) and (b) and collecting a population of microparticles, wherein (I) the population of microparticles has an maximum dimension in any one direction of between about 1 pm and about 120 pm; (II) at least about 70% of the microparticles in the population of microparticles have a maximum diameter in any one direction that is within 10% of the average particle diameter in any one direction of the population of microparticles; and (III) at least about 70% the microparticles in the composition have a maximum dimension in any one direction that is within 10% of the average dimension of the microparticle in any other one or more directions; (2) washing the population of microparticles sufficiently to eliminate at least 95% of any API in the composition which is unbound to, unencapsulated by, or otherwise unassociated with microparticles. (ASPECT 176.)

[0249] In aspects, the invention provides the method of aspect 176, wherein the first phase does not comprise a surfactant. (ASPECT 177.)

[0250] In aspects, the invention provides the method of any one or both of aspect 176 and aspect 177, wherein the second phase does not comprise a surfactant. (ASPECT 178.)

[0251] In aspects, the invention provides the method of any one or more of aspects 176 -178, wherein the second phase does not comprise a tonicity / osmolality component. (ASPECT179.)

[0252] In aspects, the invention provides the method of any one or more of aspects 176 - 179, wherein the composition resulting from the method(s) has / have any one or more of the characteristics of compositions in any one or more of aspects 1 - 76 (ASPECT 180.)

[0253] In aspects, the invention provides the method of any one or more of aspects 176 - 180, wherein the method further comprises a step for the addition of a vehicle component to form a formulation suitable for immediate administration. (ASPECT 181.)

[0254] In aspects, the invention provides the method of aspect 181, wherein the method results in a formulation having any one or more of the characteristics of any one or more of aspects 92 - 175. (ASPECT 182.)METHOD(S) OF TREATMENT

[0255] In aspects, the invention provides a method of achieving a detectable or significant reduction in body weight in a mammalian subject, wherein the method comprises parenterally administering an effective amount of any one or more of the compositions of any one or more of aspects 1 - 91; an effective amount of any one or more of the formulations of any one or more of aspects 92 - 175; a composition made by the method of manufacture of any one or more of aspects 176 - 180; or a formulation made by the method of manufacture of any one or both of aspect 181 and aspect 182, for an effective administration period, and wherein the method comprises the administration of such composition(s) or formulation(s) no more than about once per month. (ASPECT 183.)

[0256] In aspects, the invention provides a method of treating obesity in a mammalian subject, wherein the method comprises parenterally administering an effective amount of any one or more of the compositions of any one or more of aspects 1 - 91; an effective amount of any one or more of the formulations of any one or more of aspects 92 - 175; a composition made by the method of manufacture of any one or more of aspects 176 - 180; or a formulation made by the method of manufacture of any one or both of aspect 181 and aspect 182, for an effective administration period, and wherein the method comprises the administration of such composition(s) or formulation(s) no more than about once per month. (ASPECT 184.)

[0257] In aspects, the invention provides a method of treating diabetes, e.g., type II diabetes mellitus, in a mammalian subject, wherein the method comprises parenterally administering an effective amount of any one or more of the compositions of any one or more of aspects 1 - 91; an effective amount of any one or more of the formulations of any one or more of aspects 92 - 175; a composition made by the method of manufacture of any one or more of aspects 176 - 180 ; or a formulation made by the method of manufacture of any one or both of aspect 181 and aspect 182, for an effective administration period, and wherein the methodcomprises the administration of such composition(s) or formulation(s) no more than about once per month. (ASPECT 185.)

[0258] In aspects, the invention provides a method of detectably or significantly reducing fasting blood glucose levels in a mammalian subject, wherein the method comprises parenterally administering an effective amount of any one or more of the compositions of any one or more of aspects 1 - 91; an effective amount of any one or more of the formulations of any one or more of aspects 92 - 175; a composition made by the method of manufacture of any one or more of aspects 176 - 180; or a formulation made by the method of manufacture of any one or both of aspect 181 and aspect 182, for an effective administration period, and wherein the method comprises the administration of such composition(s) or formulation(s) no more than about once per month. (ASPECT 186.)

[0259] In aspects, the invention provides a method of detectably or significantly reducing hemoglobin Ale (HbAlc) levels in a mammalian subject, wherein the method comprises parenterally administering an effective amount of any one or more of the compositions of any one or more of aspects 1 - 91; an effective amount of any one or more of the formulations of any one or more of aspects 92 - 175; a composition made by the method of manufacture of any one or more of aspects 176 - 180; or a formulation made by the method of manufacture of any one or both of aspect 181 and aspect 182, for an effective administration period, and wherein the method comprises the administration of such composition(s) or formulation(s) no more than about once per month. (ASPECT 187.)

[0260] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-187, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 2 weeks. (ASPECT 188.)

[0261] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-188, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 3 weeks. (ASPECT 189)

[0262] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-189, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 4 weeks. (ASPECT 190.)

[0263] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-190, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 6 weeks. (ASPECT 191.)

[0264] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-191, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 2 months. (ASPECT 192.)

[0265] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-192, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 3 months. (ASPECT 193.)

[0266] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-193, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 4 months. (ASPECT 194.)

[0267] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-194, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 5 months. (ASPECT 195.)

[0268] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-195, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 6 months. (ASPECT 196.)

[0269] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-196, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 7 months. (ASPECT 197.)

[0270] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-197, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 8 months. (ASPECT 198.)

[0271] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183 -198, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 9 months. (ASPECT 199.)

[0272] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-199, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 10 months. (ASPECT 200.)

[0273] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183-200, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 11 months. (ASPECT 201.)

[0274] In aspects, the invention provides any one or more of the methods in any one or more of aspects 183 - 201, wherein the method(s) comprise administration of composition(s) or formulation(s) no more than about once per every 12 months. (ASPECT 202.)

[0275] In aspects, the invention provides one or more of the composition(s), formulation(s), or method(s) provided in the section entitled, “ADDITIONAL EXEMPLARY EMBODIMENTS” provided herein, wherein, further, composition(s) can further comprise any one or more of the characteristics provided in any one or more of aspects 1 - 91; formulation(s) can further comprise any one or more of the characteristics provided in any one or more of aspects 92 - 175; composition(s) can be made according to any one or more of the method(s) described in any one or more of aspects 176 - 180; formulation(s) can be made according to any one or more of the method(s) described in any one or both of aspect 181 and aspect 182. (ASPECT 203.)

[0276] A method of treatment of obesity in a patient in need thereof, comprising administering to the patient a long-acting parenteral pharmaceutical composition comprising one or more active pharmaceutical ingredients or a pharmaceutically acceptable salt thereof having detectable or significant agonist activity against one or more of melanocortin-1 receptor (MC1- R), melanocortin-2 receptor (MC2-R), melanocortin-3 receptor (MC3-R), melanocortin-4 receptor (MC4-R), melanocortin-5 receptor (MC5-R), glucagon-like peptide-1 (GLP-1) receptor; glucose-dependent insulin-tropic polypeptide (GIP) receptor; glucagon receptor, and a carrier component comprising one or more biodegradable polymers, wherein the composition is administered once every two weeks to once every six months. (ASPECT 204.)

[0277] In aspects, the invention provides the composition of any one or more of aspects 1 - 86, wherein the composition provides a twenty-four-hour Tirzepatide burst release of less than 2% of the administered dose following administration; and cumulative release at onset is <=15%. (ASPECT 205.)

[0278] In aspects, the invention provides the composition of any one or more of aspects 1 - 90, wherein the microparticles release API(s) at 37° C at a pH of 7.4 wherein a plateau is expected at 80% release. After the observed lag phase of the month, a steady release is observed that will last for approximately 2 to 3 months. (ASPECT 206.)

[0279] In aspects, the invention provides the composition of any one or more of aspects 1 - 90, wherein the microparticles release API(s) at 37° C at a pH of 7.4 wherein a plateau is expected at 80% release. After the observed lag phase of the month, a steady release is observed that will last for approximately 6 months. (ASPECT 207.)

[0280] In aspects, the invention provides the composition of any one or more of aspects 92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow- releasing microparticles, wherein the encapsulation efficiencies of at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% is obtained.(ASPECT 208.)COMPOSITION(S) / FORMULATIONS

[0281] In aspects, the invention provides the composition of any one or more of aspects 92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow- releasing microparticles, wherein the encapsulation efficiencies of more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% is obtained. (ASPECT 209.)

[0282] In aspects, the invention provides the composition of any one or more of aspects 92 - 123, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow- releasing microparticles, wherein the encapsulation efficiencies of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% is obtained. (ASPECT 210.)

[0283] In aspects, the invention provides the composition of any one or more of aspects 1 - 85, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in 50mM Phosphate buffer pH 7.4 + 13.7 mM NaCl + 0.05 %w / v BRIJ35; less than about 80% of the administered dose of API(s) is released within the first 14 days post-administration or post-placement in 50mM Phosphate buffer pH 7.4 + 13.7 mM NaCl + 0.05 %w / v BRIJ35; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or post-placement in 50mM Phosphate buffer pH 7.4 + 13.7 mM NaCl + 0.05 %w / v BRIJ35, or a combination of any or all thereof. (ASPECT 211.)

[0284] In aspects, the invention provides the formulation of any one or more of aspects 130 - 164, wherein less than about 20% of the administered dose of API(s) is released within the first 24 hours post-administration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7; less than about 80% of the administered dose of API(s) is released within the first 14 days postadministration or post-placement in phosphate buffer + 0.05% Brij 35 at pH 7; less than about 80% of the administered dose of API(s) is released within the first 28 days post-administration or postplacement in phosphate buffer + 0.05% Brij35 at pH 7; or a combination of any or all thereof. (ASPECT 212.)ADDITIONAL EXEMPLARY EMBODIMENTS

[0285] An aspect of the present invention provides a method for preparing a formulation for the treatment of obesity, diabetes (e.g., type II diabetes mellitus), or both, in which an aqueous first phase comprising about 0.1 wt.% to about 20 wt.% water soluble glucagon-like peptide-1 (GLP-1) agonist and / or glucagon receptor agonist and / or glucose-dependent insulino- tropic polypeptide (GIP) agonist and / or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or melanocortin-5 (MC5) receptor agonist is prepared as well as a second phase comprising about 5 wt.% to about 50 wt.% of a biodegradable polymer and an organic solvent is prepared. The first phase is introduced in said second phase through a membrane to form a primary (w / o) emulsion, comprising at least substantially, e.g., at least essentially monodisperse micro-droplets of said first phase in said second phase. This primary (w / o) emulsion is dispersed in a third aqueous phase to form a double (w / o / w) emulsion, comprising micro-droplets of said primary (w / o) emulsion in said third phase. More than 70% of said micro-droplets may be substantially equally sized within about 10% deviation from an average size. After removing the solvent, a composition is obtained of extremely mono-disperse micro-particles of said GLP-1 agonist and / or glucagon receptor agonist and / or GIP agonist and / or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist in a biodegradable matrix of said biodegradable polymer. This microparticle formulation may be rendered in a pharmaceutically acceptable form for subcutaneous administration.

[0286] An aspect of the present invention provides a method for preparing a formulation for the treatment of obesity, diabetes (e.g., type II diabetes mellitus), or both, in which an aqueous first phase comprising about 0.1 wt.% to about 20 wt.% water soluble glucagon-like peptide-1 (GLP-1) agonist and / or glucagon receptor agonist and / or glucose-dependent insulintropic polypeptide (GIP) agonist and / or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist is prepared as well as a second phase comprising about 5 wt.% to about 50 wt.% of a biodegradable polymer and an organic solvent is prepared. The first phase is introduced in said second phase through a membrane to form a primary (w / o) emulsion, comprising at least substantially, e.g., at least essentially monodisperse micro-droplets of said first phase in said second phase. This primary (w / o) emulsion is dispersed in a third aqueous phase to form a double (w / o / w) emulsion, comprising micro-droplets of said primary (w / o) emulsion in said third phase. More than 80% of said micro-droplets may be substantially equallysized within about 10% deviation from an average size. After removing the solvent, a composition is obtained of extremely mono-disperse micro-particles of said GLP-1 agonist and / or glucagon receptor agonist and / or GIP agonist and / or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist in a biodegradable matrix of said biodegradable polymer. This microparticle formulation may be rendered in a pharmaceutically acceptable form for subcutaneous administration.

[0287] An aspect of the present invention provides the long-acting parenteral pharmaceutical composition comprising a stable formulation of tirzepatide, wherein tirzepatide is present within the range from about 0.1 wt.% to about 10 wt.% based on the total weight of the suspension (from about 1 wt.% to about 40 wt.% based on the total weight of the microparticle / microsphere). An aspect of the present invention provides the long-acting parenteral pharmaceutical composition comprising a stable formulation of tirzepatide, wherein tirzepatide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the mi croparti cl e / microsphere) .

[0288] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 0.1 wt.% to about 3 wt.% based on the total weight of the suspension (from about 1 wt.% to about 10 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolalityadjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0289] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0290] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In anotherembodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0291] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 80. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodimentare sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0292] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 80. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0293] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the totalweight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polyvinyl alcohol. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0294] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polyvinyl alcohol. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within therange from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0295] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is carboxymethylcellulose. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0296] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is carboxymethylcellulose. The suspending agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0297] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is, in aspects, within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, thiscomposition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 1 wt.%. to about 10 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0298] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. Thebuffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0299] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is mannitol. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0300] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is mannitol. The osmolality adjusting agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0301] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.%based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0302] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0303] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0304] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is presentin an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0305] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiment, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to theembodiment is pure water. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0306] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 25 wt.% based on the total weight of the microsphere. Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 12 wt.% to about 21 wt.% based on the total weight of the microsphere. The biodegradable polymer according to the embodiment is poly (D,L-lactide-co-glycolide) (PLGA). The amount of PLGA is within the range from about 75 wt.% to about 90 wt.% based on the total weight of the microsphere. The composition of the PLGA is described based on the molar ratio of the monomers used. In another embodiment, this composition ratio is, in aspects, within 50:50 of lactic acid: glycolic acid. In another embodiment, this composition ratio is, in aspects, within 75:25 of lactic acid: glycolic acid. In another embodiment, the biodegradable polymer is poly (D,L-lactide) (PLA). In another embodiment, the amount of PLA is within the range from about 75 wt.% to about 90 wt.% based on the total weight of the microsphere. The surfactant according to the embodiment is polysorbate 20. In another embodiment, the surfactant is present in an amount within the range from about 0.01 wt.% to about 0.1 wt.% based on the total weight of the formulation. The suspending agent according to the embodiment is polyethylene glycol. In another embodiment, the suspending agent is present in an amount within the range from about 1 wt.% to about 15 wt.% based on the total weight of the suspension. In another embodiment, the suspending agent is present in an amount within the range from about 5 wt.% to about 15 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent(s) according to the embodiment is Potassium chloride. The osmolality adjusting agent(s) according to the embodiment is sodium chloride, Potassium chloride and combination thereof. The one or more osmolality adjusting agent(s) is present in an amount within the range from about 0.005 wt.% to about 1.015 wt.% based on the total weight of the suspension. The one or more osmolality adjusting agent(s) is present in an amount within the range from about 0.005 wt.% to about 1 wt.% based on the total weight of the suspension. Sodium chloride is present in an amount within the range from about 0.1 wt.% to about 1.0 wt.% based on the total weight of the suspension. Potassium chloride is present in an amount within the range from about 0.005 wt.% to about 0.015 wt.% based on the total weight of the suspension. In another embodiments, the buffering agent(s) according to the embodimentare dipotassium phosphate and sodium phosphate dibasic. The buffering agent(s) is present in an amount within the range from about 0.005 wt.% to about 0.115 wt.% based on the total weight of the suspension. The buffering agent(s) is present in an amount within the range from about 0.005 wt.% to about 0.1 wt.% based on the total weight of the suspension. The buffering agent(s) dipotassium phosphate is present in an amount within the range from about 0.005 wt.% to about 0.015 wt.% and sodium phosphate dibasic 0.01 - 0.1 wt% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0307] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 1 wt.% to about 40 wt.% based on the total weight of the microsphere. In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 10 wt.% to about 25 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The average particle size of the microspheres in the suspension of the embodiment is not more than 90 pm. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 10 pm to 80 pm.

[0308] The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0309] An embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant.

[0310] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant.

[0311] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0312] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0313] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 100 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0314] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 100 pm. The microspheres in thesuspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0315] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 30 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0316] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 10 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0317] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 30 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0318] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheresare prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 10 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0319] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 80 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0320] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 80 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 80 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0321] Another embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0322] An embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0323] An embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase optionally contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 75 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0324] An embodiment of the present invention provides the long-acting parenteral pharmaceutical composition of tirzepatide, wherein tirzepatide is present within the range from about 10 wt.% to about 25 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase optionally contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension. An embodiment of the present invention provides the long- acting parenteral pharmaceutical composition of retatrutide, wherein retatrutide is present within the range from about 1 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loadedmicrospheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0325] An aspect of the present invention provides the long-acting parenteral pharmaceutical composition comprising a stable formulation of active pharmaceutical ingredient (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmel anotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the mi croparti cl e / microsphere) .

[0326] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredient (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 0.1 wt.% to about 3 wt.% based on the total weight of the suspension (from about 1 wt.% to about 10 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to theembodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0327] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0328] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used, this composition ratio is within 70:30 and 85: 15of lactic acid: glycolic acid. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agentaccording to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0329] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 80. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to theembodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0330] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 80. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0331] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer is PLGA. Theamount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polyvinyl alcohol. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0332] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used, this composition ratio is within 70:30 and 85: 15of lactic acid: glycolic acid. The surfactant according to the embodiment is polyvinyl alcohol. The surfactant is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in anamount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0333] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is carboxymethylcellulose. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in anamount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0334] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is carboxymethylcellulose. The suspending agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0335] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 1 wt.% to about 10 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0336] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymeris PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0337] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is mannitol. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrateand citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0338] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is mannitol. The osmolality adjusting agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0339] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% toabout 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0340] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratiois within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0341] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. Thebuffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0342] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are di-sodium hydrogen phosphate and sodium hydroxide. The buffering agent(s) is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is water for injection. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0343] Another aspect of the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from retatrutide, setmelanotide, pemvidutide,lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the suspension (from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere). The biodegradable polymer according to the embodiment is PLGA. The amount of PLGA is within the range of about 25 wt.% to about 45 wt.% based on the total weight of the suspension (present in an amount within the range from about 55 wt.% to about 95 wt.% based on the total weight of the microsphere). The composition of the PLGA is described based on the molar ratio of the monomers used. This composition ratio is within 70:30 and 85: 15 of lactic acid: glycolic acid. In another embodiment, this composition ratio is within 50:50 of lactic acid: glycolic acid. In another embodiments, this composition ratio is within 75:25 of lactic acid: glycolic acid. In another embodiments, the biodegradable polymer is PLA. The surfactant according to the embodiment is polysorbate 20. The surfactant is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The suspending agent according to the embodiment is polyethylene glycol. The suspending agent is present in an amount within the range from about 1 wt.% to about 5 wt.% based on the total weight of the suspension. The osmolality adjusting agent(s) according to the embodiment is sodium chloride. The osmolality adjusting agent is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The buffering agent(s) according to the embodiment are sodium dihydrogen phosphate monohydrate and citric acid. The buffering agent(s) is present in an amount within the range from about 0.1 wt.% to about 1 wt.% based on the total weight of the suspension. The vehicle according to the embodiment is pure water. The vehicle(s) is present in an amount within the range from about 60 wt.% to about 80 wt.% based on the total weight of the suspension.

[0344] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 1 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0345] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant.

[0346] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant.

[0347] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0348] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension haveparticle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0349] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 100 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0350] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant and buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 100 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have an average particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0351] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 30 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shapee.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0352] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 30 pm to 80 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0353] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 80 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0354] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from about 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains buffering agents. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 80 pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 80 % of the loaded microspheres in the suspension have particle sizethat is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0355] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 3 wt.% to about 10 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have a particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0356] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 10 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1 pm to 40 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0357] In an embodiment, the present invention provides the long-acting parenteral pharmaceutical composition of active pharmaceutical ingredients (API), wherein one or more active pharmaceutical ingredients (APIs) selected from tirzepatide, retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide is present within the range from 4 wt.% to about 40 wt.% based on the total weight of the microsphere. The microspheres are prepared using w / o / w emulsion technique in which the inner water phase optionally contains a surfactant. The average particle size of the microspheres in the suspension of the embodiment is in the range from about 1pm to 120 pm. The microspheres in the suspension are substantially uniform in size and shape e.g., about 70 % of the loaded microspheres in the suspension have a particle size that is within (+ / -) 10% of the size of the average particle size of the loaded microspheres in the suspension.

[0358] In an aspect, provided are compositions characterized by any one or more of the above-provided aspects, wherein the composition is further characterized by lacking one or more components of the compositions described in, or by having an amount of one or more component(s) of a composition that is significant different or sizably different from the amount of one or more component(s) described in, any one or more of WO2023281495,W02010028257, EP4205728, W02022003662, or any of the references cited in the Background of this disclosure.BRIEF DESCRIPTION OF THE FIGURES:

[0359] Figure 1 provides an SEM image showing inner morphology of Tirzepatide- loaded microspheres.

[0360] Figure 2 provides SEM images at different magnifications showing the outer morphology of Tirzepatide-loaded microspheres.

[0361] Figure 3 provides In-vitro release data of Tirzepatide-loaded microspheres at 45°C in pH 7, pH 9 buffered systems and at 37°C in pH 7.4 buffered systems.

[0362] Figure 4 provides the volume average diameter measured by coulter counter method for Tirzepatide-loaded microsphere formulation.DETAILED DESCRIPTION OF THE INVENTION

[0363] For convenience, both combinations of elements / steps and individual elements / steps may be described in this section of this disclosure. Despite the inclusion of passages focused on specific elements / steps, any aspect, facet, embodiment, or other description of particular step(s) or element(s) can be applied to any general description of the compositions / methods of the invention, or any other recited element(s) / step(s) thereof, which are provided in any part of this disclosure.

[0364] As used herein, the word "exemplary" means "serving as an example, instance, or illustration." The following detailed description is merely exemplary in nature and is not intended to limit application and uses. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

[0365] There is a need to develop a long-acting injection of drugs like melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or melanocortin-5 (MC5)receptor agonist and / or GLP-1 and / or GIP and / glucagonreceptor agonist which offer the release of such drug over a prolonged period of time, which may exceed more than a month or even several months. Pharmaceutical composition(s) of the present invention offers patient compliance and predictable and stable plasma levels.

[0366] The inventors have surprisingly identified composition(s) of microparticles comprising one or more API(s) characterizable as an agonist at one or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors or which is an agonist at one or more of glucagon-like peptide- 1 (GLP-1); glucose-dependent insulin-tropic polypeptide (GIP); and glucagon receptor, or combination(s) thereof, which, when provided in formulation(s) for parenteral administration, provide controlled, long-acting drug release. In embodiments, composition(s) and formulation(s) provided herein can: (1) comprise component(s) and constituent s); be made by method(s) / process(es); be used in method(s) of treatment; and, e.g., be component(s) of kit(s), all of which are described herein.

[0367] The inventors have surprisingly identified composition(s) of microparticles comprising one or more API(s) is selected from tirzepatide, retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide or combination(s) thereof, which, when provided in formulation(s) for parenteral administration, provide controlled, long- acting drug release. In embodiments, composition(s) and formulation(s) provided herein can: (1) comprise component s) and constituent s); be made by method(s) / process(es); be used in method(s) of treatment; and, e.g., be component(s) of kit(s), all of which are described herein. Reference to “composition(s)” herein is, generally, used to describe population(s) of microparticles (microparticle compositions or microparticulate composition(s)). Use of the term “composition” can refer to specific composition(s) of microparticles alone (e.g., without the presence of a vehicle component) or when present as a component of formulation(s) (e.g., in the presence of a vehicle component). Characteristics of “composition(s)” described herein should be interpreted as being characteristic(s) of formulation(s) when such composition(s) is / are a component thereof. Reference to “formulation(s)” herein is, generally, used to describe microparticle compositions plus a vehicle such that a formulation is a composition is in administrable form, administrable form being, e.g., a form suitable for parenteral administration to a mammalian recipient.Composition(s) & Formulation(s)Microparticle Compositions)

[0368] In aspects, the invention provides composition(s) of microparticles comprising one or more API(s) wherein the microparticles provide for the controlled, long term release such API(s). In aspects, microparticle composition(s) provided herein are long-acting, parenterally administered composition(s) comprising an API component and a carrier component.

[0369] In certain aspects, the present invention provides a long-acting, parenteral pharmaceutical composition comprising a population of microparticles comprising (1) an API component comprising GLP-1 and / or glucagon and / or GIP agonist(s) or other incretin hormone agonist or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist or other melanocortin agonist; (2) a carrier component comprising one or more biodegradable polymer(s); and (3) a surfactant component comprising one or more surfactant(s) / surf actant agent(s). In aspects, one or more component(s) or constituent(s) thereof can, at least in part or, e.g., completely, reside within (be a part of) one or more other component(s). For example, in aspects, a surfactant component can be encompassed by or be a constituent of a carrier component.

[0370] Herein, “GLP-1 and / or glucagon and / or GIP agonist(s)” refers to one or more compounds providing one or more such agonist activity(ies). For example, “GLP-1 and / or glucagon and / or GIP agonist(s)” can refer to one or more compound(s) wherein each compound demonstrates one of GLP-1 agonist activity, glucagon receptor activity, or GIP agonist activity; or, e.g., “GLP-1 and / or glucagon and / or GIP agonist(s)” can refer to one or more compound(s) wherein each compound demonstrates two or more of GLP-1 agonist activity, glucagon receptor activity, and GIP agonist activities.

[0371] Herein, “melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or melanocortin-5 (MC5) receptor agonist agonist(s)” refers to one or more compounds providing one or more such agonist activity(ies). For example, “ melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist(s)” can refer to one or more compound(s) wherein each compound demonstrates one of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors; or, e.g., “melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist(s)” can refer to one or more compound(s) wherein each compound demonstrates two or more of melanocortin-1 (MCI) activity; melanocortin-2 (MC2) activity;melanocortin-3 (MC3) activity; melanocortin-4 (MC4) activity; and melanocortin-5 (MC5) receptors activities.

[0372] In certain aspects, the present invention provides long-acting, parenteral pharmaceutical composition(s) comprising a population of microparticles comprising (1) an API component comprising GLP-1 and / or glucagon and / or GIP agonist(s) and / or melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) receptor agonist, (2) a carrier component comprising one or more biodegradable polymer(s); (3) a surfactant component comprising one or more surfactant(s); (4) a suspension component comprising one or more suspending agent(s); (5) an osmolality component comprising one or more osmolality agent(s); (6) a buffer component and (7) a vehicle component comprising one or more vehicle(s) to form formulation(s), formulation(s) being further described elsewhere herein. As described above, in aspects, one or more component(s) or constituent s) thereof can, at least in part or, e.g., completely, reside within (be a part of) one or more other component s). For example, in aspects, a suspension component can be encompassed by or be a constituent of a vehicle component.

[0373] In certain aspects, the present invention provides long-acting, parenteral pharmaceutical composition(s) comprising a population of microparticles comprising (1) one or more API(S) is selected from tirzepatide, retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide; (2) a carrier component comprising one or more biodegradable polymer(s); (3) a surfactant component comprising one or more surfactant s); (4) a suspension component comprising one or more suspending agent(s); (5) an osmolality component comprising one or more osmolality agent(s); (6) a buffer component and (7) a vehicle component comprising one or more vehicle(s) to form formulation(s), formulation(s) being further described elsewhere herein. As described above, in aspects, one or more component s) or constituent s) thereof can, at least in part or, e.g., completely, reside within (be a part of) one or more other component(s). For example, in aspects, a suspension component can be encompassed by or be a constituent of a vehicle component.Active Pharmaceutical Ingredient Component (Means for applying agonist activity / agonist means)

[0374] In one aspect, the invention provides composition(s) comprising a population of microparticles wherein the microparticle(s) comprise an API component, one or more API(s), wherein the API(s) comprise one or more of a melanocortin-1 receptor (MCI) agonist;melanocortin-2 receptor (MC2) agonist; melanocortin-3 receptor (MC3) agonist; melanocortin-4 receptor (MC4) agonist; melanocortin-5 receptor (MC5) agonist; GLP-1 agonist; glucagon receptor agonist; GIP agonist, or compound(s) demonstrating activity at two or more of a GLP-1 agonist, a glucagon receptor agonist, and a GIP agonist activity or compound(s) demonstrating activity at two or more of a melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor agonist.Active Pharmaceutical Ingredient s) (API(s))

[0375] According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), e.g., peptide API(s). In one aspect, composition(s), e.g., microparticle composition(s) and formulation(s) comprising such microparticle composition(s) of the invention are characterized by, i.a., that most, generally all, substantially all, or all of the peptide active pharmaceutical ingredient compound(s) of the microparticles have a molecular weight of at least about 1000 Da, such as at least about -1100 Da, -1200 Da, -1300 Da, -1400 Da, -1500 Da, -1600 Da, -1700 Da, -1800 Da, or at least about -1900 Da. In one aspect, composition(s), e.g., microparticle composition(s) and formulation(s) comprising such microparticle composition(s) of the invention are characterized by, i.a., that most, generally all, substantially all, or all of the peptide active pharmaceutical ingredient compound(s) of the microparticles have a molecular weight of at least about 2000Da, such as at least about — 2100 Da, -2200 Da, -2300 Da, -2400 Da, -2500 Da, -2600 Da, -2700 Da, -2800 Da, or at least about -2900 Da. In one aspect, composition(s), e.g., microparticle composition(s) and formulation(s) comprising such microparticle composition(s) of the invention are characterized by, i.a., that most, generally all, substantially all, or all of the peptide active pharmaceutical ingredient compound(s) of the microparticles have a molecular weight of at least about 3000Da, such as at least about — 3100 Da, -3200 Da, -3300 Da, -3400 Da, -3500 Da, -3600 Da, -3700 Da, -3800 Da, or at least about -3900 Da. In aspects, most, generally all, substantially all, or all of the API(s) in most, generally all, substantially all, or all of the microparticles of a composition have a molecular weight of at least about 4000Da, such as at least about -4100 Da, -4200 Da, -4300 Da, -4400 Da, -4500 Da, -4600 Da, 4700 Da, 4800 Da, or at least about 4900 Da.

[0376] In aspects, most, generally all, substantially all, or all of the API(s) in most, generally all, substantially all, or all of the microparticles of a composition have a molecular weight of -1000 Da - -5000 Da, -1200 Da - -5000 Da, -1400 Da - -5000 Da, -1600 Da - -5000 Da, -1800 Da - -5000 Da, -2000 Da - -5000 Da, -2200 Da - -5000 Da, -2400 Da - -5000 Da, -2600 Da --5000 Da, -2800 Da - -5000 Da, -3000 Da - -5000 Da, -3200 Da - -5000 Da, -3400 Da - -5000 Da, -3500 Da - -5000 Da, -3600 Da - -4850 Da, -3700 Da - -4700 Da, -3800 Da - -4600 Da, -3900 Da - -4500 Da.

[0377] In aspects, most, generally all, substantially all, or all of the API(s) in most, generally all, substantially all, or all of the microparticles of a composition have a molecular weight of -4250 Da - -5000 Da, -4300 Da - -4950 Da, -4350 Da - -5950 Da, -4400 Da - -5000 Da, -4500 Da - -5000 Da, -4600 Da - -5000 Da, or, e.g., -4650-4850 Da.

[0378] According to aspects, composition(s) (and by default, formulation(s) comprising such composition(s); which should be understood accordingly throughout this disclosure) provided herein can comprise one or more agonists of blood sugar controlling hormone(s). In aspects, composition(s) comprise one or more API(s), e.g., one or more antidiabetic API(s) suitable for use in the treatment of type 2 diabetes; one or more API(s) suitable for use in treating obesity; one or more API(s) suitable for detectably or significantly improving blood sugar control; or combination(s) of any or all thereof.

[0379] In aspects, the API is a water-soluble API. GLP-1, glucagon, and GIP are hormones involved in blood sugar control. Glucagon-like peptide- 1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) are representative gastrointestinal hormones and neuronal hormones and are materials involved in the control of blood glucose levels according to food intake. Glucagon is a peptide hormone secreted by the pancreas and is involved in controlling the blood glucose levels.

[0380] GLP-1 is a hormone secreted by the small intestine stimulated by food intake. GLP-1 promotes insulin secretion in the pancreas in a blood glucose-dependent manner and inhibits the secretion of glucagon, thus helping the action of lowering blood glucose levels. Additionally, GLP-1 has the roles of slowing digestive action in the gastrointestinal tract by acting as a satiety factor and reducing the amount of food intake by delaying the time for emptying digested food in the gastrointestinal tract.

[0381] GIP, one of the gastrointestinal hormones secreted by the stimulation of food intake as is the case of GLP-1, is a hormone consisting of 42 amino acids secreted by the intestinal K-cells. GIP was reported to perform the functions of promoting the secretion of insulin in the pancreas in a blood glucose-dependent manner and helping to lower the blood glucose levels, thereby exhibiting the effects of increasing the activation of GLP-1, antiinflammation, etc.

[0382] Glucagon is produced in the pancreas when the blood glucose levels fall due to reasons such as medications, diseases, deficiency in hormones or enzymes, etc. Glucagon sends a signal for glycogen breakdown in the liver to induce the release of glucose and increases blood glucose levels to a normal level. In addition to the effect of increasing the blood glucose levels, glucagon suppresses appetite in animals and humans and activates hormone-sensitive lipase of adipocytes to promote lipolysis and energy expenditure, thereby showing an anti-obesity effect.

[0383] In aspects, composition(s) and formulation(s) herein comprise one or more glucagon-like peptide-1 (GLP-1) agonist(s); one or more glucose-dependent insulin-tropic polypeptide (GIP) agonists; one or more glucagon receptor agonist(s); combinations or any or all thereof; or compound(s) demonstrating multiple such agonist activity(ies). A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MCI) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3 and MC4) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5), expressed in a wide distribution of peripheral tissues. MCI has been suggested to be associated with hair and skin pigmentation and inflammation, MC2 is believed to mediate steroidogenesis, MC3 has been suggested to be associated with energy homeostasis, food intake, and inflammation, MC4 is believed to control feeding behavior, energy homeostasis, and sexual function (e.g. erectile function), and MC5 has been suggested to be involved in the exocrine gland system. The compounds specific for MC3, MC4 or MC5 are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other treatment of other food intake and metabolism-related purposes. In aspects, most, generally all, substantially all, or all the API(s) in the composition(s) and formulation(s) described herein are ligands for at least one if not two or more endogenous molecules / targets (e.g., for glucagon receptor, glucosedependent insulinotropic polypeptide receptor, and GLP-1 receptor).

[0384] In aspects, most, generally all, substantially all, or all the API(s) in the composition(s) and formulation(s) described herein are ligands for at least one if not two or more endogenous molecules / targets (e.g. for melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor ).

[0385] In aspects, most, generally all, substantially all, or all the API(s) in the composition(s) and formulation(s) described herein are ligands for at least one if not two ormore endogenous molecules / targets (e.g. for melanocortin-1 receptor (MCI), melanocortin-2 receptor (MC2), melanocortin-3 receptor (MC3), melanocortin-4 receptor (MC4), melanocortin- 5 receptor (MC5), glucagon receptor, glucose-dependent insulinotropic polypeptide receptor, and GLP-1 receptor).

[0386] In this respect, such ligands typically show a detectable or significant binding to such molecule(s) / target(s) (which often are receptors, and, accordingly, the word receptor herein can be used interchangeably with and as simultaneously disclosing other ligands and vice versa). In some respects, such API(s) exhibit DOS biological / physiological responses associated with such binding to ligands. In aspects, the APIs exhibit at least about 80%, at least about 85%, at least about 95%, or about 100% of the same activity for the API administered in a “free” stage (i.e., not associated with the microparticles). In aspects, the microparticle API(s) maintain such levels of binding efficacy for a sustained period (e.g., at least 3, 6, 9, 12, 15, or 18 months after administration).

[0387] In aspects, API(s) present in composition(s) herein can comprise GLP-1 and / or glucagon and / or GIP agonist(s) selected from (1) API(s) that act as a GLP-1 agonist; (2) API (s) that act as a glucagon / glucagon receptor agonist; (3) API (s) that act as a GIP agonist; (4) API (s) that act as both a GLP-1 agonist and a glucagon / glucagon receptor agonist; API (s) that act as both a GLP-1 agonist and a GIP agonist; (5) API (s) that act as both a glucagon / glucagon receptor agonist and a GIP agonist; or (6) API (s) that act as a GLP-1 agonist, a glucagon / glucagon receptor agonist, and a GIP agonist

[0388] In aspects, API(s) present in composition(s) herein can comprise melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or melanocortin-5 (MC5) receptor agonist(s).

[0389] In aspects, API(s) present in composition(s) herein can comprise (l)API (s) that act as a melanocortin-1 receptor (MCI) agonist (2)API (s) that act as a melanocortin-2 receptor (MC2) agonist (3) API (s) that act as a melanocortin-3 receptor (MC3) agonist (4) API (s) that act as a melanocortin-4 receptor (MC4) agonist (5) API (s) that act as a melanocortin-5 receptor (MC5) agonist.

[0390] In aspects, composition(s) provided by the invention comprise a single API wherein the single API demonstrates detectable or significant agonist activity of only one of GLP-1, glucagon receptors, and GIP.

[0391] In aspects, composition(s) provided by the invention comprise a single API wherein the single API demonstrates detectable or significant agonist activity of only one ofmelanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor.

[0392] In aspects, composition(s) comprise two or more APIs each demonstrating detectable or significant agonist activity of only one of GLP-1, glucagon receptors, and GIP.

[0393] In aspects, composition(s) comprise two or more APIs each demonstrating detectable or significant agonist activity of only one of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor.

[0394] In aspects, composition(s) comprise a single API wherein the single API demonstrates detectable or significant agonist activity of two or more of GLP-1, glucagon receptors, and GIP.

[0395] In aspects, composition(s) comprise a single API wherein the single API demonstrates detectable or significant agonist activity of two or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors.

[0396] In aspects, composition(s) comprise two or more APIs wherein each of the two or more APIs demonstrate detectable or significant agonist activity of two or more of GLP-1, glucagon receptors, and GIP.

[0397] In aspects, composition(s) comprise two or more APIs wherein each of the two or more APIs demonstrate detectable or significant agonist activity of two or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors.

[0398] In aspects, composition(s) comprise two or more APIs wherein at least one of the two or more APIs demonstrates detectable or significant activity of only one of GLP-1, glucagon receptors, and GIP, while at least one other of the two or more APIs demonstrates detectable or significant activity of two or more of GLP-1, glucagon receptors, and GIP.

[0399] In aspects, composition(s) comprise two or more APIs wherein at least one of the two or more APIs demonstrates detectable or significant activity of only one of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors, while at least one other of the two or more APIs demonstrates detectable or significant activity of two or more of melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptors.GLP-1 agonist(s) (GLP-1 activation means)

[0400] According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant GLP-1 agonist activity. In aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that function as a GLP-1 -analogue; i.e., the API(s) functionally mimic the action of the human incretin glucagon-like peptide- 1 (GLP-1), resulting in the detectable or significant increase in insulin secretion, the detectable or significant increase in blood sugar disposal, the detectable or significant improvement in glycemic control, or any or all thereof. In aspects, composition(s) provided herein comprise an API component comprising a means for activating GLP-1. In aspects, composition(s) provided herein comprise a GLP-1 activation means. According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant GLP-1 agonist activity, i.e., a means for activating GLP-1, i.e., a GLP-1 activation means, such as, e.g., lixisenatide, dulaglutide, liraglutide, albiglutide, retatrutide, pemvidutide, or tirzepatide, etc. In aspects, composition(s) provided herein comprise an API component comprising lixisenatide, dulaglutide, liraglutide, albiglutide, retatrutide, pemvidutide, or tirzepatide, or a combination of any or all thereof.

[0401] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GLP-1 agonist activity, but which does / do not demonstrate detectable or significant GIP agonist activity, glucagon receptor agonist activity, or both, such as, e.g., lixisenatide, dulaglutide, liraglutide, albiglutide, etc. In aspects, composition(s) provided herein comprise an API component comprising lixisenatide, dulaglutide, liraglutide, albiglutide, or a combination of any or all thereof.

[0402] In certain aspects, composition(s) do not comprise any API(s) which demonstrate detectable or significant GLP-1 agonist activity but do not demonstrate detectable or significant glucagon receptor agonist activity, GIP agonist activity, or both. For example, in aspects, composition(s) provided herein do not comprise lixisenatide, dulaglutide, liraglutide, or albiglutide, or a combination of any or all thereof.Glucagon receptor agonist(s) (Glucagon receptor activation means)

[0403] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant glucagon receptor agonist activity. In aspects, composition(s) provided herein comprise an API component comprising oneor more API(s), capable of detectable or significantly activating the glucagon receptor by mimicking the action of the human hormone glucagon. In aspects, composition(s) provided herein comprise an API component comprising one or more means for activating glucagon receptors. In aspects, composition(s) provided herein comprise and API component comprising a glucagon receptor activation means. In aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant glucagon receptor agonist activity, i.e., a means for activating glucagon receptors, i.e., glucagon receptor activation means, such as, e.g., retatrutide, pemvidutide, etc. In aspects, composition(s) provided herein comprise an API component comprising retatrutide, pemvidutide, or a combination thereof.

[0404] In aspects, composition(s) provided herein do not comprise any API(s) which demonstrate detectable or significant GLP-1 agonist activity, detectable or significant GIP agonist activity, or both, but do not demonstrate detectable or significant glucagon receptor agonist activity. For example, in aspects, composition(s) provided herein do not comprise lixisenatide, dulaglutide, liraglutide, albiglutide, or, e.g., tirzepatide.

[0405] In aspects, composition(s) provided herein do not comprise any API(s) which demonstrate detectable or significant glucagon receptor agonist activity and detectable or significant GLP-1 activity, but which does / do not demonstrate detectable or significant GIP agonist activity. For example, in aspects, composition(s) provided herein does / do not comprise pemvidutide. In aspects, composition(s) provided herein comprise an API component comprising retatrutide.GIP agonist(s) (GIP activation means)

[0406] According to certain aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant GIP agonist activity. In aspects, composition(s) provided herein comprise an API component comprising a means for activating GIP. In aspects, composition(s) provided herein comprise a GIP activation means. According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant GIP agonist activity, i.e., a means for activating GIP, i.e., a GIP activation means, such as, e.g., retatrutide, tirzepatide, etc. In aspects, composition(s) provided herein comprise an API component comprising retatrutide, tirzepatide, or a combination thereof.

[0407] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GIP agonist activity, but which does / do not demonstrate detectable glucagon receptor agonist activity, such as, e.g., tirzepatide. In aspects, composition(s) provided herein comprise an API component comprising retatrutide.

[0408] In some aspects, composition(s) provided herein do not comprise any API(s) which demonstrate detectable or significant GLP-1 agonist activity, glucagon receptor agonist activity, or both, but which do not demonstrate detectable or significant GIP agonist activity. For example, in aspects, composition(s) do not comprise lixisenatide, dulaglutide, liraglutide, albiglutide, or pemvidutide.Multiple target agonist(s) (Multi-target Agonist Means)

[0409] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that each provide detectable or significant agonist activity of two or more of GLP-1, glucagon receptors, and GIP. In certain aspects, composition(s) provided herein, e.g., microparticle composition(s) comprising one or more such API(s), such as, e.g., retatrutide, tirzepatide, or both, surprisingly demonstrate agonist activity of two or more of GLP- 1, glucagon / glucagon receptors, and GIP when provided in such a form. In aspects, microparticle composition(s) provide API(s) such as, e.g., retatrutide, tirzepatide, or, e.g., one or more API(s) described herein which demonstrate agonist activity of GLP-1, glucagon receptors and GIP for an extended period of time, e.g., a period of at least about 1 month, e.g., such as a period of at least about 3, about 6, about 9, or, e.g., at least about 12 months. In aspects, composition(s) provided herein comprise an API component comprising a means for activating two or more of GLP-1, glucagon receptors, and GIP. In aspects, composition(s) provided herein comprise a GLP-1 and glucagon receptor activation means; a GLP-1 and GIP activation means; a glucagon receptor and GIP activation means; a GLP-1, glucagon receptor, and GIP activation means; or a combination of any or all thereof. According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), e.g., peptide API(s), that provide detectable or significant agonist activity of two or more of GLP-1, glucagon receptors, and GIP, such as, e.g., retatrutide, tirzepatide, etc. In aspects, composition(s) provided herein comprise an API component comprising retatrutide, tirzepatide, or a combination of any or all thereof.

[0410] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GLP-1 agonist activity and detectable or significant glucagon receptor agonist activity, such as, e.g., retatrutide, pemvidutide, etc. In aspects, composition(s) provided herein comprise an API component comprising retatrutide, pemvidutide, or both.

[0411] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GLP-1 agonist activity and detectable or significant GIP agonist activity, such as, e.g., retatrutide, tirzepatide, etc. In aspects, composition(s) provided herein comprise an API component comprising retatrutide, tirzepatide, or both.

[0412] In aspects, composition(s) provided herein do not comprise any API which does not demonstrate detectable or significant activity of two or more of GLP-1, glucagon receptors, and GIP, such as, e.g., lixisenatide, dulaglutide, liraglutide, or albiglutide.

[0413] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant agonist activity of two or more of GLP-1, glucagon receptors, and GIP, but which does / do not demonstrate detectable or significant agonist activity of each of GLP-1, glucagon receptors, and GIP, such as, e.g., pemvidutide, tirzepatide, etc. In aspects, composition(s) provided herein comprise an API component comprising pemvidutide, tirzepatide, or both.

[0414] In certain aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant agonist activity of each of GLP-1, glucagon receptors, and GIP, such as, e.g., retatrutide. In one specific aspect of the present invention, the invention provides a stable, long-acting release microparticle formulation of a glucagon-like peptide-1 (GLP-1) agonist and / or glucagon receptor agonist and / or glucose-dependent insulin-tropic polypeptide (GIP) agonist. In aspects, composition(s) provided herein comprise an API component comprising retatrutide.

[0415] In certain aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GLP-1 and GIP agonist activity, but which does / do not demonstrate detectable glucagon receptor agonist activity, such as, e.g., tirzepatide. In aspects, composition(s) provided herein comprise an API component comprising tirzepatide.

[0416] In certain aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant GLP-1 and glucagonreceptor activity, but which does / do not demonstrate detectable or significant GIP agonist activity, such as, e.g., pemvidutide. In aspects, composition(s) provided herein comprise an API component comprising pemvidutide.Melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor agonist(s)(Melanocortin-1 (MCI), melanocortin-2 (MC2), melanocortin-3 (MC3), melanocortin-4 (MC4), and melanocortin-5 (MC5) receptor activation means)

[0417] According to certain aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant MCI, MC2, MC3, MC4, and MC5 receptor agonist activity. In aspects, composition(s) provided herein comprise an API component comprising a means for activating MCI, MC2, MC3, MC4, and MC5 receptor. In aspects, composition(s) provided herein comprise a MCI, MC2, MC3, MC4, and MC5 receptor activation means. According to aspects, composition(s) provided herein comprise an API component comprising one or more API(s), that provide detectable or significant MC4 agonist activity, i.e., a means for activating MC4 receptor, i.e., a MC4 activation means, such as, e.g., setmelanotide, etc. In aspects, composition(s) provided herein comprise an API component comprising setmelanotide.In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) which demonstrate detectable or significant MC4 receptor agonist activity, but which does / do not demonstrate detectable MCI; MC2; MC3; and MC5 receptor agonist activity, such as, e.g., setmelanotide. In aspects, composition(s) provided herein comprise an API component comprising setmelanotide.API - Particle Content: API(s)

[0418] According to certain aspects, composition(s) provided herein comprise an API component comprising a single API, and microparticle(s) in composition(s) provided herein comprise the single API. In aspects, compositions can, therefore, comprise a single population of microparticles wherein the microparticles have at least mostly, at least generally, at least substantially, at least essentially, or the same content with regard to API.

[0419] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s). In aspects, composition(s) provided herein comprise one or more API(s), such as, e.g., one or more API(s) selected from a group comprising tirzepatide, retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide,wherein a detectable or significant amount of each of the at least one or more API(s) is present on, within, or is otherwise is associated with some, most, generally all, substantially all, essentially all, or all particle(s) of the composition, such that the microparticles of the composition have at least mostly, at least generally, at least substantially, at least essentially, or the same content with regard to APIs. In aspects, composition(s) provided herein comprise microparticles wherein at least most, generally all, substantially all, essentially all, or all microparticles of the composition comprise the same API(s).

[0420] In aspects, composition(s) provided herein comprise an API component comprising one or more API(s) selected from a group comprising tirzepatide, retatrutide, setmel anotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide, wherein at least one of the at least two APIs is provided on, within, or is provided as otherwise associated with a first sub-population of microparticles, while at least one of the at least two APIs is provided on, within, or is provided as otherwise associated with a second sub-population of microparticles.

[0421] In aspects, composition(s) provided herein comprise microparticles wherein at least a first portion of the microparticles in the composition represent a first sub-population of microparticles, and at least a second portion of the microparticles in the composition represent a second sub-population of microparticles, wherein the at least first and at least second population of particle(s) differ in their API content; e.g., at least one sub-population of microparticles comprises at least one API which is not present in at least one other sub-population of microparticles.

[0422] In aspects wherein composition(s) provided by the invention comprise at least two sub-populations of microparticles, each subpopulation can represent any percentage of the full microparticle population of the composition. For example, in aspects, a composition can comprise, e.g., two sub-populations of microparticles wherein the first sub-population represents about 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more than 95% of the full population of microparticles (e.g., about 0.1% - at least 95%, such as, e.g., -0.1 - -90%, -0.1 - -80%, -0.1 - -70%, -0.1 - -60%, -0.1 - -50%, -0.1 - -40%, -0.1 - -30%, -0.1 - -20%, -0.1 - -10%, or, e.g., -0.1% - 5% of the full population, such as -5% - -95%, -10% - -95%, -20% - -95%, -30% - -95%, -40% - -95%, -50% - -95%, -60% - -95%, -70% - -95%, -80% - -95%, or, e.g., -90% - -95% of the full population, e.g., -5% - -90%, -10% - -80%, -20% - -70%, -30% - -60%, or, e.g., -40% - -50%, and, e.g., any values near or encompassed by such ranges asdescribed elsewhere herein), while the second sub-population represents the remainder of the full population of microparticles. Similarly, in aspects, for example, composition(s) can comprise three or more sub-population(s) if microparticles wherein each sub-population of microparticles can represent any fraction of the full population of microparticles, and the combination of the sub-populations represents the full population of microparticles in the composition.Active Pharmaceutical Ingredient(s) (API(s)) - Amount

[0423] The API component of composition(s) provided herein can be present in any effective amount, such as, e.g., any effective amount suitable and effective in the treatment of (e.g., effective in detectably or significantly advantageously modifying one or more indicators of) a disease state or condition over the course of a treatment period.

[0424] In aspects, the API component of composition(s) provided herein can comprise API(s) (an API component) in an amount effective to detectably or significantly treat (e.g., detectably or significantly advantageously modify one or more indicators of) diabetes, e.g., type- 2 diabetes mellitus, or side effects associated therewith, or condition(s) related thereto, when administered over the course of an effective treatment period.

[0425] The API component of composition(s) provided herein can comprise API(s) (an API component) in an amount effective to detectably or significantly treat (e.g., detectably or significantly advantageously modify one or more indicators of) obesity or side effect(s) associated therewith, or condition(s) related thereto, when administered over the course of an effective treatment period.

[0426] The API component of composition(s) provided herein can comprise API(s) (an API component) in an amount effective to detectably or significantly reduce body weight or condition(s) related excess thereof, when administered over the course of an effective treatment period.

[0427] The API component of composition(s) provided herein can comprise API(s) (an API component) in an amount effective to detectably or significantly reduce blood sugar level(s), i.e., fasting glucose level(s), or condition(s) related thereto, when administered over the course of an effective treatment period. The API component of composition(s) provided herein can comprise API(s) in an amount effective to detectably or significantly reduce blood sugar level(s), i.e., fasting glucose level(s), by at least about 5%, such as, e.g., >~6%, >~8%, >~10%,>~15%, >~20%, >~25%, >~30%, >~35%, >~40%, >~45%, or, e.g., >~50% over the course of an effective treatment period.

[0428] The API component of composition(s) provided herein can comprise API(s) (an API component) in an amount effective to detectably or significantly reduce hemoglobin Ale (HbAlc), or condition(s) related thereto, when administered over the course of an effective treatment period. The API component of composition(s) provided herein can comprise API(s) in an amount effective to detectably or significantly reduce HbAlc, by at least about 5%, such as, e.g., >~6%, >~8%, >~10%, >~15%, >~20%, >~25%, >~30%, >~35%, >~40%, >~45%, or, e.g., >~50% over the course of an effective treatment period.

[0429] According to certain aspects, composition(s) are prepared using a doubleemulsion preparation method comprising a first phase. In aspects, the first phase is an aqueous first phase. In aspects, composition(s) are prepared using a double-emulsion preparation method comprising a first phase wherein one or more API(s) (an API component) is / are present in the first phase in an amount representing between about 0.1 wt.% and about 30 wt.%, such as, e.g., -0.1 wt.% - ~28 wt.%, -0.1 wt.% - ~26 wt.%, -0.1 wt.% - ~24 wt.%, -0.1 wt.% - -22 wt.%,-0.1 wt.% - ~20 wt.%, -0.1 wt.% - -18 wt.%, -0.1 wt.% - -16 wt.%, -0.1 wt.% - -14 wt.%,-0.1 wt.% - -12 wt.%, -0.1 wt.% - -10 wt.%, -0.1 wt.% - ~8 wt.%, -0.1 wt.% - -6 wt.%, -0.1 wt.% - -4 wt.%, or, e.g., -0.1 wt.% - -2 wt.% of the first phase.

[0430] In aspects, the first phase is an aqueous first phase. In aspects, composition(s) are prepared using a double-emulsion preparation method comprising a first phase wherein one or more API(s) (an API component) is / are present in the first phase in an amount representing between about 0.2 wt.% and about 30 wt.%, such as, e.g., ~0.4 wt.% - -30 wt.%, -0.6 wt.% - -30 wt.%, -0.8 wt.% - -30 wt.%, -1 wt.% - -30 wt.%, -2 wt.% - -30 wt.%, -4 wt.% - -30 wt.%, -6 wt.% - -30 wt.%, -8 wt.% - -30 wt.%, -10 wt.% - -30 wt.%, -12 wt.% - -30 wt.%, -14 wt.% - -30 wt.%, -16 wt.% - -30 wt.%, -18 wt.% - -30 wt.%, -20 wt.% - -30 wt.%, -22 wt.% - -30 wt.%, -24 wt.% - -30 wt.%, -26 wt.% - -30 wt.%, or -28 wt.% - -30 wt.%, of the first phase.

[0431] In aspects, the first phase is an aqueous first phase. In aspects, composition(s) are prepared using a double-emulsion preparation method comprising a first phase wherein one or more API(s) (an API component) is / are present in the first phase in an amount representing between about 0.2 wt.% and about 30 wt.%, such as, e.g., -0.4 wt.% - -28 wt.%, -0.6 wt.% - -26 wt.%, -0.8 wt.% - -24 wt.%, -1 wt.% - -22 wt.%, -2 wt.% - -20 wt.%, -4 wt.% - -18wt.%, -6 wt.% - -16 wt.%, ~8 wt.% - -14 wt.%, or, e.g., -10 wt.% - -12 wt.%, of the first phase.

[0432] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 0.1 wt.% and about 20 wt.% of the suspension, such as, e.g., -0.1 wt.% - -18 wt.%, -0.1 wt.% - -16 wt.%, -0.1 wt.% - -14 wt.%, -0.1 wt.% - -12 wt.%, -0.1 wt.% - -10 wt.%, -0.1 wt.% - ~8 wt.%, -0.1 wt.% - -6 wt.%, -0.1 wt.% - -4 wt.%, -0.1 wt.% - -3 wt.%, or, e.g., -0.1 wt.% - -2 wt.% of the formulation(s), e.g., of the suspension(s).

[0433] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 0.2 wt.% - ~20 wt.%, ~0.4 wt.% - -20 wt.%, -0.6 wt.% - -20 wt.%, -0.8 wt.% - -20 wt.%, -1 wt.% - -20 wt.%, -2 wt.% - -20 wt.%, -4 wt.% - -20 wt.%, -6 wt.% - -20 wt.%, -8 wt.% - -20 wt.%, -10 wt.% - -20 wt.%, -12 wt.% - -20 wt.%, -14 wt.% - -20 wt.%, -16 wt.% - -20 wt.%, or -18 wt.% - -20 wt.% of the formulation(s), e.g., of the suspension(s).

[0434] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 0.2 wt.% and about 18 wt.%, such as, e.g., -0.4 wt.% - -16 wt.%, -0.6 wt.% - -14 wt.%, -0.8 wt.% - -12 wt.%, -1 wt.% - -10 wt.%, -2 wt.% - -10 wt.%, or, e.g., -3 wt.% - -10 wt.% of the formulation(s), e.g., suspension(s).

[0435] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 1 wt.% and about 50 wt.% of the microparticle(s), such as, e.g., -1 wt.% - -45 wt.%, -1 wt.% - -40 wt.%, -1 wt.% - -35 wt.%, -1 wt.% - -30 wt.%, -1 wt.% - -25 wt.%, -1 wt.% - -20 wt.%, -1 wt.% - -15 wt.%, -1 wt.% - -10 wt.%, or, e.g., -1 wt.% - -5 wt.% of the microparticle(s).

[0436] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 2 wt.% - -50 wt.%, -5 wt.% - -50 wt.%, -10 wt.% - -50 wt.%, -15 wt.% - -50 wt.%, -20 wt.% - -50 wt.%,~25 wt.% - ~50 wt.%, ~30 wt.% - ~50 wt.%, ~35 wt.% - ~50 wt.%, ~40 wt.% - ~50 wt.%, or, e.g., ~45 wt.% - ~50 wt.% of the microparticles.

[0437] According to certain aspects, formulation(s) provided by the invention, e.g., formulation(s) provided as suspensions (e.g., suspension(s) of microparticle composition(s)) can comprise API(s) (an API component) in an amount representing between about 2 wt.% and about 48 wt.%, such as, e.g., ~4 wt.% - ~46 wt.%, ~6 wt.% - ~44 wt.%, ~8 wt.% - ~42 wt.%, ~10 wt.% - ~40 wt.%, ~12 wt.% - ~38 wt.%, ~14 wt.% - ~36 wt.%, ~16 wt.% - ~34 wt.%, ~18 wt.% - ~32 wt.%, ~20 wt.% - ~30 wt.%, or, e.g., ~22 wt.% - ~28 wt.% of the microparticle(s).

[0438] In some aspects, one or more melanocortin-1 (MCI) and / or melanocortin-2 (MC2) and / or melanocortin-3 (MC3) and / or melanocortin-4 (MC4) and / or and melanocortin-5 (MC5) agonist(s)and / or GLP-1 and / or glucagon and / or GIP agonist(s), present as an API component, is(are) present in an amount of between about 0.1 wt.% and about 20 wt.% based on the total weight of a formulation provided as a suspension (present in an amount of between about 1 wt.% and about 50 wt.% based on the total weight of the microparticle(s)). In certain aspects, the API component is present in an amount of between about 1 wt.% and about 15 wt.% of the formulation(s), e.g., of suspension(s), (between about 1 wt.% and about 45 wt.% based on the total weight of the microparticle(s)).

[0439] In certain further aspects, the API component is present in an amount of between about 1 wt.% and about 15 wt.% of formulation(s), e.g., of suspension(s), (between about 1 wt.% and about 40 wt.% based on the total weight of the microparticle(s)).

[0440] In certain further aspects, the API component is present in an amount of between about 1 wt.% and about 15 wt.% of formulation(s), e.g., of suspension(s), (between about 4 wt.% and about 15 wt.% based on the total weight of the microparti cle(s)).

[0441] In certain further aspects, the API component is present in an amount of between about 3 wt.% and about 10 wt.% of formulation(s), e.g., of suspension(s), (between about 1 wt.% and about 40 wt.% based on the total weight of the microparticle(s)).In certain further aspects, the API component is present in an amount of between about 3 wt.% and about 10 wt.% of formulation(s), e.g., of suspension(s), (between about 4 wt.% and about 15 wt.% based on the total weight of the microparticle(s)).

[0442] In certain aspects, the API component is present in an amount of between about 1 wt.% and about 40 wt.% based on the total weight of the microparticle(s).

[0443] In certain aspects, the API component is present in an amount of between about 4 wt.% and about 15 wt.% based on the total weight of the microparti cle(s).

[0444] In specific aspects, composition(s) comprise less than about 10%, such as, e.g., <~9%, <~8%, <~7%, <~6%, <~5%, <~4%, <~3%, <~2%, or, e.g., <~1% of any API component (e.g., of any one or more API(s) present in the formulation(s)) which is / are unbound to, unattached to, unencapsulated by, or otherwise unassociated with microparticle(s) (e.g., API characterizable as “free” API).Carrier Component (Means of Controlled API Delivery / API Delivery Means)

[0445] In aspects, composition(s) provided herein comprise a carrier component. In aspects, the carrier component provides a means of delivering an API component. In aspects, the carrier component provides a means of delivering an API component without a detectable or significant burst effect, e.g., without a detectable or significant initial rapid release of API(s) and in controlled manner over an extended period of time. Herein, the term “controlled,” as in controlled release or release in a controlled manner means the release of API(s) at an average rate over any continuous 24-hour period after a single dose that does not vary from the average rate of release of the same API(s) over any other 24-hour period after the same single dose by more than about 20%, such as by more than about 15%, more than about 10%, more than about 5%, more than about 1%.

[0446] In aspects, microparticle composition(s) provided herein are long-acting, parenterally administered composition(s) comprising an API component and a carrier component. In aspects, a carrier component can comprise any one or more constituents capable of releasing API(s) of an API component in a controlled matter over an extended period of time. In aspects, a carrier component comprises one or more polymer(s). In aspects, the carrier component comprises one or more biodegradable polymer(s), i.e., polymer(s) which degrade over time in-vivo or under mimicked physiological condition(s).

[0447] In aspects, composition(s) provided herein comprise one or more polymer(s), e.g., one or more biodegradable polymer(s), comprising, e.g., poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyethylene glycol (PEG), polycarbonate(s) (PC(s)), polyorthoester(s) (POE(s)), polyesteramide(s) (PEA(s)), N-(2-hydroxypropyl) methacrylamide (HPMA), polyglutamic acid (PGA), polyalkyl cyanoacrylate, polycaprolactone (PCL), polyhydroxybutyric acid, polyvalonic acid, polyanhydride, polyhydroxybutyratehydroxyvalerate, polylactic acid-polyethylene glycol, polyglycolic acid-polyethylene glycol, polysaccharides, polypeptides, proteins, etc., or mixtures of any or all thereof, e.g., mixture(s) of these polymers, or, e.g., block-co-polymers thereof.

[0448] In certain aspects, composition(s) comprise a carrier component comprising a single biodegradable polymer. In aspects, composition(s) comprise a carrier component comprising a combination of two or more polymers. In aspects, composition(s) comprise a carrier component comprising PLGA. In aspects, PLGA is the only biodegradable polymer of a carrier component. In aspects, PLGA is the only polymer of a carrier component.Polymer Carrier — Molar Ratio of PLGA

[0449] In aspects, formulation(s), composition(s), or microparticles therein comprise a carrier component comprising a biodegradable polymer, e.g., PLGA. In aspects, PLGA characterizable according to the molar ratio of the monomers of which it is comprised, lactic acid and glycolic acid. In aspects, the composition of monomers for PLGA in a carrier component is within a ratio of between about 50:50 and 100:0 of lactic acid : glycolic acid (written in an alternative form, 50-100 : 0-50), such as, for example, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85: 15, 90: 10, or, e.g., 95:5. In aspects, the composition of monomers for PLGA in a carrier component is between about 55:45 and about 95:5, between about 75:25 and about 25:75, between about 60:40 and about 90: 10, between about 65:35 and about 85: 15, between about 70:30 and about 80:20 lactic acid : glycolic acid. In aspects, the composition of monomers for PLGA in a carrier component is between about 50:50 and about 75:25 lactic acid : glycolic acid.Carrier Amount

[0450] According to aspects, a carrier component (or, e.g., constituent(s) thereof, such as, for example, PLGA, can be present in any amount effective in forming microparticles suitable for the delivery of API(s) according to the characteristic(s) of delivery provided herein.

[0451] In aspects, microparticles of composition(s) provided herein are formed using a double-emulsion technology, wherein, in a second phase, a carrier material, e.g., a polymer, e.g., a biodegradable polymer, e.g., PLGA, is dissolved in a solvent, such as a suitable oil solvent (e.g., forming an oil phase of the double-emulsion process.)

[0452] In aspects, the polymer fraction of a phase of a double emulsion can represent an amount of between about 5 wt.% and about 50 wt.% of the phase, e.g., second (e.g., second oil) phase, as in, e.g., ~5 wt.% - ~45 wt.%, ~5 wt.% - ~40 wt.%, ~5 wt.% - ~35 wt.%, ~5 wt.% - ~30 wt.%, ~5 wt.% - ~25 wt.%, ~5 wt.% - ~20 wt.%, ~5 wt.% - ~15 wt.%, or, e.g., ~5 wt.% - ~10 wt.% of the polymer dissolution phase.

[0453] In aspects, the polymer fraction of a phase of a double emulsion can represent an amount of between about 10 wt.% and about 50 wt.% of the phase, e.g., second (e.g., second oil) phase, as in, e.g., ~15 wt.% - ~50 wt.%, ~20 wt.% - ~50 wt.%, ~25 wt.% - ~50 wt.%, ~30 wt.% - ~50 wt.%, ~35 wt.% - ~50 wt.%, ~40 wt.% - ~50 wt.%, or, e.g., ~45 wt.% - ~50 wt.% of the polymer dissolution phase.

[0454] In aspects, the polymer fraction of a phase of a double emulsion can represent an amount of between about 10 wt.% and about 45 wt.% of the phase, e.g., second (e.g., second oil) phase, as in, e.g., ~12 wt.% - ~48 wt.%, ~14 wt.% - ~46 wt.%, ~16 wt.% - ~44 wt.%, ~18 wt.% - ~42 wt.%, ~20 wt.% - ~40 wt.%, ~22 wt.% - ~38 wt.%, ~24 wt.% - ~36 wt.%, or, e.g., ~26 wt.%- ~34 wt.% of the polymer dissolution phase.

[0455] In aspects, the polymer fraction of a phase of a double emulsion can represent an amount of between about 10 wt.% and about 30 wt.% of the phase, e.g., second (e.g., second oil) phase, as in, e.g., ~12 wt.% - ~28 wt.%, ~14 wt.% - ~26 wt.%, ~16 wt.% - ~24 wt.%, or ~18 wt.% - ~22 wt.%, of the polymer dissolution phase.

[0456] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 10 wt.% and about 70 wt.% of a total weight of a formulation, e.g., suspension, such as, e.g., ~10 wt.% - ~65 wt.%, ~10 wt.% - ~60 wt.%, ~10 wt.% - ~55 wt.%, ~10 wt.% - ~40 wt.%, ~10 wt.% - ~35 wt.%, ~10 wt.%- ~30 wt.%, ~10 wt.% - ~25 wt.%, ~10 wt.% - ~20 wt.%, or, e.g., ~10 wt.% - ~15 wt.% of a total formulation, e.g., suspension.

[0457] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 15 wt.% and about 70 wt.% of a total weight of a formulation, e.g., suspension, such as, e.g., ~20 wt.% - ~70 wt.%, ~25 wt.% - ~70 wt.%, ~30 wt.% - ~70 wt.%, ~35 wt.% - ~70 wt.%, ~40 wt.% - ~70 wt.%, ~45 wt.%- ~70 wt.%, ~50 wt.% - ~70 wt.%, ~55 wt.% - ~70 wt.%, ~60 wt.% - ~70 wt.%, or, e.g., ~65 wt.% - ~70 wt.% of a total formulation, e.g., suspension.

[0458] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 15 wt.% and about 65 wt.% of a total weight of a formulation, e.g., suspension, such as, e.g., ~20 wt.% - ~55 wt.%, ~25wt.% - ~55 wt.%, ~25 wt.% - ~50 wt.%, ~30 wt.% - ~45 wt.%, or, e.g., ~35 wt.% - ~40 wt.% of a total formulation, e.g., suspension.

[0459] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 55 wt.% and about 95 wt.% of the total weight of microparticle(s) such as, e.g., ~55 wt.% - 90 wt.%, ~55 wt.% - 85 wt.%, ~55 wt.% - 80 wt.%, ~55 wt.% - 75 wt.%, ~55 wt.% - 70 wt.%, ~55 wt.% - 65 wt.%, or, e.g., ~55 wt.% - 60 wt.%, of the total weight of microparti cle(s).

[0460] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 60 wt.% and about 95 wt.% of the total weight of microparticles, ~65 wt.% - ~95 wt.%, ~70 wt.% - ~95 wt.%, ~75 wt.% - ~95 wt.%, ~80 wt.% - ~95 wt.%, ~85 wt.% - ~95 wt.%, or, e.g., ~90 wt.% - ~95 wt.%, of the total weight of microparticle(s).

[0461] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, representing between about 60 wt.% and about 90 wt.% of the total weight of microparticle(s), such as, e.g., ~65 wt.% - ~85 wt.%, or, e.g., ~70 wt.% - ~80 wt.% of the total weight of microparticle(s).

[0462] In aspects, formulation(s) or composition(s) can comprise a carrier component comprising one or more carrier material(s), e.g., one or more polymer(s), e.g., one or more biodegradable polymer(s), e.g., PLGA, PLA representing between about 75 wt.% and about 90 wt.% of the total weight of microparticle(s) , such as, e.g., ~75 wt.% - ~80 wt.%, ~88 wt.% - ~85 wt.%, or, e.g., ~85...

Claims

CLAIMS1. A method of treatment of obesity in a patient in need thereof, comprising administering to the patient a long-acting parenteral pharmaceutical composition comprising one or more active pharmaceutical ingredients or a pharmaceutically acceptable salt thereof having detectable or significant agonist activity against one or more of melanocortin-1 (MCI) receptor, melanocortin-2 (MC2) receptor, melanocortin-3 (MC3) receptor, melanocortin-4 (MC4) receptor, melanocortin-5 (MC5) receptor, glucagon-like peptide-1 (GLP-1) receptor, glucosedependent insulin-tropic polypeptide (GIP) receptor, glucagon receptor, and a carrier component comprising one or more biodegradable polymers, wherein the composition is administered once every two weeks to once every six months.

2. The method of claim 1, wherein a long-acting parenteral pharmaceutical composition comprising monodisperse microsphere particles having an average particle size not more than 120 pm and at least about 70% of the particles have a particle size within 10% of the average particle size.

3. The method of claim 1 or 2, wherein a long-acting parenteral pharmaceutical composition comprising monodisperse microsphere particles having an average particle size not more than 100 pm and at least about 70% of the particles have a particle size within 10% of the average particle size.

4. The method of any one of the preceding claims, wherein a long-acting parenteral pharmaceutical composition comprising monodisperse microsphere particles having an average particle size not more than 90 pm and at least about 70% of the particles have a particle size within 10% of the average particle size.

5. The method of any one of the preceding claims, wherein a long-acting parenteral pharmaceutical composition comprising monodisperse microsphere particles having an average particle size between about 30pm and 80 pm and at least about 70% of the particles have a particle size within 10% of the average particle size.

6. The method of any one of the preceding claims, wherein a long-acting parenteral pharmaceutical composition comprises one or more active pharmaceutical ingredients selectedfrom a group comprising tirzepatide, retatrutide, setmelanotide, pemvidutide, lixisenatide, dulaglutide, liraglutide, and albiglutide.

7. The method of any one of the preceding claims, wherein one or more active pharmaceutical ingredients is present in the microparticles of the formulation in an amount between about 1 wt.% and about 40 wt.% of the microparticles.

8. The method of any one of the preceding claims, wherein one or more active pharmaceutical ingredients is present in the microparticles of the formulation in an amount between about 4 wt.% and about 15 wt.% of the microparticles.

9. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises a carrier component, wherein the carrier compound is poly(lactic-co- glycolic acid) (PLGA).

10. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered once in less than 6 months, less than 4 months, less than 3 months, less than 2 months, less than 1 month, once every four weeks or once every two weeks.

11. The method of any one of the preceding claims, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 45 degrees.

12. The method of any one of the preceding claims, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 40 degrees.

13. The method of any one of the preceding claims, wherein active pharmaceutical ingredient is encapsulated in a biodegradable slow-releasing microparticles, wherein the microparticles are in the form of free-flowing powder having an angle of repose less than about 35 degrees.

14. The method of any one of claims 11-13, wherein the powder is reconstituted in a physiologically acceptable solvent.

15. The method of claim 14, wherein the powder is reconstituted in a non-aqueous phase.

16. The method of any one of claims 11-13, wherein the free-flowing powder is readily dispersible and injected with a static mixing device in a pen-injector.

17. The method of any one of the preceding claims, wherein the composition is provided in pre-filled syringe, vial or pre-filled injector.

18. The method of claim 17, wherein the pre-filled injector is a pen injector or an autoinjector.

19. The method of claim 17 or 18, wherein the pre-filled injector is equipped with 28G-32G needles.

20. The method of any one of claims 17-19, wherein the pre-filled injector is used to self-administer the microsphere formulation.

Images