Pharmaceutical composition of polymeric micelle cinacalcet as well as preparation method and application of pharmaceutical composition

Abstract

Pharmaceutical compositions of polymeric micelle cinacalcet suitable for intravenous or intraperitoneal administration, and methods of making and use thereof in the treatment of various diseases and disorders, such as hyperparathyroidism and hypercalcemia, are provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 581,901, filed with the U.S. Patent and Trademark Office on September 11, 2023, entitled “Pharmaceutical Compositions of Polymeric Micellar Cinacalcet, Methods for Preparation and Use Thereof,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application generally relates to pharmaceuticals and therapeutic methods. More specifically, the present application provides pharmaceutical compositions of polymeric micelle cinacalcet, methods for their preparation, and uses in treating various diseases and conditions (e.g., hyperparathyroidism and hypercalcemia). Background Art

[0004] Cinacalcet is a calcimimetic that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. For example, cinacalcet is used to reduce parathyroid hormone (PTH), serum calcium, serum phosphorus, and the calcium-phosphorus product in patients with chronic kidney disease and secondary hyperparathyroidism undergoing dialysis, and to reduce the elevations in serum calcium associated with primary hyperparathyroidism and parathyroid carcinoma.

[0005] Trademark and Existing commercial cinacalcet products sold by, etc. are formulated as solid tablets and are administered orally. Studies have shown that solid tablets of cinacalcet are poorly absorbed. When taken orally, cinacalcet dissolves in the stomach where the pH is low, but it can precipitate in the lower GI (gastrointestinal) tract where the pH is higher. Therefore, the dissolution and bioavailability of cinacalcet tablets are not optimal, the bioavailability is low, and the pharmacokinetic profiles are highly variable. The absolute bioavailability of cinacalcet in fasting subjects is estimated to be 20-25%. (EMEA Mimpara Product Characteristics Summary - Section 5.2 Pharmacokinetic Properties, https: / / www.ema.europa.eu / en / documents / product-information / mimpara-epar-pr oduct-information_en.pdf) FDA and EMEA issued and Labeling information includes a recommendation to take cinacalcet with or shortly after food. If patients fail to follow directions, cinacalcet may result in subtherapeutic doses. Patient compliance with oral cinacalcet has been a significant challenge.

[0006] To improve patient compliance, various attempts have been made to develop intravenous formulations, as they can be conveniently administered during dialysis. However, the poor water solubility and blood compatibility of cinacalcet have hindered the development of intravenous formulations. One example of such an effort is to dissolve cinacalcet in oil and then emulsify it in water (Gore et al., 2014, U.S. Patent 8,779,004). However, oil-in-water emulsions have poor stability and difficulty controlling particle size distribution. In addition, the ability of emulsion formulations to achieve sustained circulation in the blood is limited.

[0007] To date, a suitable intravenous formulation of cinacalcet has not been successfully developed. There remains an urgent need for a suitable intravenous formulation of cinacalcet to help improve patient compliance and treatment outcomes. Summary of the Invention

[0008] This application is based, in part, on the discovery of polymeric micellar formulations of cinacalcet that are suitable for intravenous or intraperitoneal administration, such as during dialysis. The polymeric micellar cinacalcet formulations disclosed herein exhibit dilution stability, hemocompatibility, improved safety by reducing injection site reactions, effectively reduce PTH levels, and can be easily and economically produced.

[0009] More specifically, provided herein are pharmaceutical formulations of cinacalcet, methods for preparing the same, and uses thereof. The disclosed pharmaceutical formulations and treatment methods are suitable for delivering cinacalcet to patients suffering from diseases requiring treatment with cinacalcet. The pharmaceutical formulations of the present application comprise cinacalcet dissolved in an amphiphilic block copolymer, and other excipients, such as one or more buffers, cryoprotectants and lyoprotectants or fillers, and surfactants. The polymer micellar cinacalcet compositions of the present application can be formulated into a stable lyophilized form for long-term storage. Upon reconstitution, colloidal polymer micelles suitable for injection are formed. We have found that cyclodextrin and its derivatives effectively protect micelles composed of water-insoluble polymers and prevent micelle aggregation.

[0010] Polymeric micelle formulations can be readily prepared by mixing an organic solution of cinacalcet / block copolymer with an aqueous buffer solution. The solvent can optionally be removed by evaporation, and other excipients can be added as needed. Alternatively, the polymeric micelle formulation can be prepared by dissolving cinacalcet and the block copolymer in an organic solvent, removing the solvent by evaporation under vacuum and moderate heating to form a solid matrix, and reconstituted with an aqueous buffer solution optionally containing a lyoprotectant or filler. The micelle solution can be lyophilized and reconstituted before use. The micelle formulation is stable after freezing and / or lyophilization and is stable during long-term storage.

[0011] These formulations are hemocompatible, thus avoiding phlebitis and alleviating pain during intravenous administration. The micellar formulation can prolong the circulation time of cinacalcet in the blood. The formulation is suitable for parenteral administration, such as intravenous or intraperitoneal administration, to patients undergoing dialysis, thereby improving patient compliance compared to oral cinacalcet tablets. The pharmaceutical formulation can be used for any condition sensitive to cinacalcet treatment, such as controlling PTH levels in renal dialysis patients.

[0012] In one aspect, the present application generally relates to pharmaceutical compositions of cinacalcet, comprising micelles containing cinacalcet or a pharmaceutically acceptable salt thereof, and at least one amphiphilic block copolymer.

[0013] In another aspect, the present application generally relates to unit dosage forms comprising the pharmaceutical compositions.

[0014] In yet another aspect, the present application generally relates to a method for controlling PTH levels, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0015] In yet another aspect, the present application generally relates to a method for regulating calcium and phosphorus in the blood, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0016] In yet another aspect, the present application generally relates to a method for treating primary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0017] In yet another aspect, the present application generally relates to a method for treating secondary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0018] In yet another aspect, the present application generally relates to a method for treating parathyroid cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0019] In another aspect, the present application generally relates to a method for preparing a composition of a polymeric micelle drug disclosed herein, the method comprising: dissolving at least one amphiphilic block copolymer and a hydrophobic drug or a pharmaceutically acceptable salt thereof in an organic solvent to form a first mixture; while stirring, adding the first mixture to water or an aqueous solution; optionally removing the organic solvent to obtain a transparent to translucent colloidal micelle; and optionally adding one or more pharmaceutically acceptable excipients, carriers or diluents. The micelle formulation can also be lyophilized to remove water and solvent (if present). The micelle formulation can be frozen or refrigerated for storage after lyophilization and is stable during long-term storage.

[0020] In another aspect, the present application generally relates to another method for preparing a composition of polymeric micelle cinacalcet disclosed herein, comprising: dissolving at least one amphiphilic block copolymer and a hydrophobic drug or a pharmaceutically acceptable salt thereof in an organic solvent to form a first mixture; removing the organic solvent by evaporation to form a matrix; adding water or an aqueous solution to the matrix to obtain transparent to translucent colloidal micelles; and optionally adding one or more pharmaceutically acceptable excipients, carriers, or diluents. The micelle formulation can also be lyophilized to remove water. The micelle formulation can be stored frozen or refrigerated after lyophilization and is stable during long-term storage.

[0021] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in controlling PTH levels.

[0022] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in regulating calcium and phosphorus in the blood.

[0023] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating primary hyperparathyroidism.

[0024] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating secondary hyperparathyroidism.

[0025] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating hypercalcemia.

[0026] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in controlling parathyroid hormone (PTH) levels.

[0027] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in regulating calcium and phosphorus in the blood.

[0028] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating primary hyperparathyroidism.

[0029] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating secondary hyperparathyroidism.

[0030] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating parathyroid cancer.

[0031] In yet another aspect, the present application generally relates to cinacalcet or a pharmaceutically acceptable salt thereof and at least one amphiphilic block copolymer for use in preparing a medicament.

[0032] Notably, the compositions of the present application are easy to produce, stable after freezing and lyophilization, and stable during long-term storage. The pharmaceutical composition is blood compatible and reduces phlebitis and pain when administered intravenously. The selected amphiphilic copolymer can provide sustained release of cinacalcet and increase circulation time in the blood, thereby reducing the frequency of administration. The pharmaceutical formulation can be conveniently administered intravenously during dialysis, and can improve patient compliance, enhance bioavailability, and reduce the variability of pharmacokinetic parameters compared to oral cinacalcet tablet formulations, thereby eliminating the "food effect." BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 A flow chart illustrating an exemplary manufacturing process for preparing the formulations of the present application is shown.

[0034] Figure 2 An exemplary polymer molecular weight distribution for PDLLA-MePEG 2-2 (Batch NB009-029) is shown.

[0035] Figure 3 An exemplary particle size distribution of cinacalcet polymer micelles is shown.

[0036] Figure 4 Some exemplary data are shown for the prolonged in vitro release of cinacalcet from the polymeric micelle formulation of the present application, through a 12-14 kD dialysis membrane into 20 mM PBS buffer, pH 7.4, containing 0.1% PS80. The temperature was maintained at 37°C.

[0037] Figure 5a-5b Certain exemplary data showing the improved blood compatibility of the formulations of the present application are presented.

[0038] Figure 6 Shown are some exemplary data for the physical stability of liquid polymeric micellar cinacalcet formulations (CO, CP, CR, CT, DO, DP, DR, DS, DU, DV) stored frozen at -20° C. The turbidity of thawed and 15-fold diluted samples is shown as a function of storage time.

[0039] Figure 7 Shown are some exemplary data for the physical stability of a lyophilized polymeric micellar cinacalcet formulation (DX) stored at 2-8° C. The turbidity of a reconstituted and 15-fold diluted sample is shown as a function of storage time.

[0040] Figure 8 Shown is the reduction in PTH levels in adult male SD rats following intravenous administration of cinacalcet on days 1, 3, 5, and 8 (Rat Study 1).

[0041] Figure 9 a-9f show the plasma drug concentration profiles after intravenous administration of cinacalcet in male SD rats (rat study 2).

[0042] Figure 10 Rat body weights are shown, with weight gain being different and lower in the cinacalcet buffered solution group (rat study 3).

[0043] Figure 11 The diameter of the rat tail close to the body is shown, demonstrating that the polymer micelle formulation of cinacalcet reduced swelling and inflammation (rat study 4).

[0044] definition

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, preferred methods and materials are now described. The methods described herein can be implemented in any order that is logically possible, in addition to the specific order disclosed.

[0046] Reference throughout this specification to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0047] The features, structures or characteristics described in the applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the specification herein, many specific details are described for ease of thorough understanding of the embodiments of the application. However, those skilled in the relevant art will recognize that the applicant's compositions and / or methods may be implemented with one or more specific details omitted, or with other methods, components, materials, etc. In other examples, known structures, materials or operations are not shown or described in detail to avoid obscuring various aspects of the disclosure.

[0048] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0049] This disclosure references and cites patents, patent applications, patent publications, journals, books, papers, web content, and other documents. All of these documents are hereby incorporated by reference in their entirety for all purposes. Any material or portion thereof that is stated to be incorporated by reference herein but conflicts with existing definitions, statements, or other public materials explicitly set forth herein will be incorporated only to the extent that the incorporated material does not conflict with the material of this disclosure. In the event of a conflict, this disclosure will be used as the preferred disclosure to resolve the conflict.

[0050] As used herein, "at least" a particular value is understood to mean that value and all values ​​greater than that value.

[0051] When used to define compositions and methods, the term "comprising" is intended to mean that these compositions and methods include the listed elements, but do not exclude other elements. When used to define compositions and methods, the term "consisting essentially of shall mean that the compositions and methods include the listed elements, and exclude other elements that have any substantial significance for the compositions and methods. For example, "consisting essentially of" refers to the pharmacologically active agents that are explicitly listed, and excludes pharmacologically active agents that are not explicitly listed. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When used to define compositions and methods, the term "consisting of" shall mean excluding trace elements and substantial method steps of other ingredients. Embodiments defined by each of the above transition terms are within the scope of the present invention.

[0052] Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. Approximately can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. Unless the context clearly indicates otherwise, all numerical values ​​provided herein may be modified by the term about.

[0053] As used herein, the term "administration" of a disclosed compound encompasses delivering a compound described herein, or a salt or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration discussed herein.

[0054] Unless otherwise indicated, the terms "disease," "disorder," and "condition" are used interchangeably.

[0055] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" generally refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is used to carry or transport a pharmaceutical formulation of interest from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0056] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0057] In one or more embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. "Pharmaceutically acceptable salts" of the compounds described herein include salts formed when the compounds are mixed with inorganic or organic acids or bases. In some embodiments, salts can be prepared in situ during the final isolation and purification of the compound. In other embodiments, salts can be prepared from the free form of the compound by a separate synthesis step. The preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is detailed in "Pharmaceutical Salts" by Berg et al., J. Pharm. Sci., 1977: 66: 1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of the compounds described herein are salts that can be used in medicine. However, non-pharmaceutically acceptable salts can still be used to prepare pharmaceutically acceptable salts of the compounds described herein.

[0058] The compounds described herein or their pharmaceutically acceptable salts may contain asymmetric carbon atoms, for example, due to deuterium substitution or for other reasons. Thus, the compounds of the present invention may exist as a single enantiomer or a mixture of two enantiomers. Thus, the compounds of the present invention may exist as a racemic mixture or a non-racemic mixture, or as a single stereoisomer that is substantially free of other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means that there are less than 25% other stereoisomers, preferably less than 10% other stereoisomers, more preferably less than 5% other stereoisomers and most preferably less than 2% other stereoisomers. For a given compound, methods for obtaining or synthesizing a single enantiomer are known in the art and can be applied to the final product or starting material or intermediate.

[0059] In one or more embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that, for example, may include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein encompasses compounds and solvates of compounds, and mixtures thereof.

[0060] As used herein, the term "stable" when used to describe a compound or pharmaceutical composition means that the compound or pharmaceutical composition has sufficient chemical and physical stability to enable its manufacture and to maintain the integrity of the compound or pharmaceutical composition for a period of time sufficient to achieve its intended purpose as detailed herein (e.g., formulation into a therapeutic product, treatment of a disease or condition responsive to a therapeutic agent).

[0061] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is to be the recipient of a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably herein to refer to a human individual in need of treatment.

[0062] As used herein, the term "therapeutic effect" refers to the therapeutic benefits and / or prophylactic benefits described herein. A prophylactic effect includes delaying or eliminating the occurrence of a disease or condition, delaying or eliminating the appearance of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0063] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended application, including but not limited to disease treatment, as described below. The therapeutically effective amount may vary depending on the intended application or the subject and disease condition being treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the weight and age of the patient, which can be readily determined by one of ordinary skill in the art. The therapeutically effective amount may vary depending on the intended application or the subject and disease condition being treated, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the weight and age of the patient, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on factors such as the specific compound selected, the species of the subject and their age / existing health condition or health condition risk, the dosing regimen followed, the severity of the disease, whether it is used in combination with other agents, the timing of administration, the tissue to which the drug is administered, and the physical delivery system employed.

[0064] As used herein, the term "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after the onset of such condition. Treatment can be directed to one or more effects or symptoms of the disease and / or underlying condition. Treatment is intended to obtain beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated. In addition, therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, although the patient may still be suffering from the underlying disorder. In order to obtain a prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk for a particular disease, or to patients who report the occurrence of one or more physiological symptoms of the disease, even if the disease has not yet been diagnosed. Treatment can be any degree of relief and can be, but is not limited to, the complete elimination of the disease or disease symptoms. Such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as compared to an equivalent untreated control as measured by any standard technique.

[0065] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions that are equal to or greater than 95% ("substantially pure") by weight, which are then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention is greater than 99%. DETAILED DESCRIPTION

[0066] The detailed description, specific embodiments and examples are provided by way of illustration and not limitation. Those skilled in the art will readily recognize that various noncritical parameters can be changed or modified to produce substantially similar results. All publications, patents and patent applications cited herein, including quotations therein, are incorporated herein by reference in their entirety for all purposes.

[0067] The present application provides a stable polymeric micelle formulation of cinacalcet suitable for intravenous or intraperitoneal administration to patients suffering from a disease requiring treatment with cinacalcet. The pharmaceutical formulation of the present application comprises cinacalcet solubilized by an amphiphilic block copolymer, and other excipients, such as one or more buffers, cryoprotectants or fillers, and surfactants.

[0068] The polymer micelle formulation of the present application is blood-compatible and can prevent phlebitis and relieve pain when administered intravenously. The formulation of the present application can prolong the circulation time of cinacalcet in the blood and is suitable for parenteral administration to patients during dialysis, such as intravenous or intraperitoneal administration, which can improve patient compliance compared to oral cinacalcet tablets. In addition, the formulation of the present application exhibits stability after dilution and during long-term storage, is blood-compatible, circulates in the blood for a long time, does not cause phlebitis or pain, and has suitable pharmacokinetic characteristics (e.g., long-lasting and low variability), and can also be easily and economically produced.

[0069] The polymer micelle formulations of the present application are readily prepared by one of the following methods: 1) combining an organic solution of cinacalcet / block copolymer with an aqueous buffer solution, then optionally evaporating the solvent and adding other excipients as needed; or 2) combining an organic solution of cinacalcet / block copolymer, evaporating the solvent, then dissolving the drug / block copolymer matrix in an aqueous buffer solution and adding other excipients as needed. The micelle formulations of the present application are stable after freezing and / or lyophilization and are stable during long-term storage.

[0070] The pharmaceutical preparations of the present application can be used to treat diseases that are sensitive to treatment with cinacalcet, such as controlling PTH levels in patients on renal dialysis. More generally, the cinacalcet formulations disclosed herein can be used to treat hyperparathyroidism (elevated PTH levels) and its symptoms. Hyperparathyroidism is an overactivity of the parathyroid glands, resulting in an overproduction of PTH. PTH regulates calcium and phosphate levels and helps maintain these levels. Overactivity of one or more of the parathyroid glands leads to high calcium levels (hypercalcemia) and low phosphate levels in the blood. Hyperparathyroidism may be the result of parathyroid tumors and chronic renal failure.

[0071] Cinacalcet has the chemical structure shown below, with the chiral center in the R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to exert pharmacodynamic activity (https: / / www.pi.amgen.com / ~ / media / amgen / repositorysites / pi-amgen-com / sensipar / sensipar_pi_hcp_english.pdf).

[0072]

[0073] (R)-N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine

[0074] The polymer micelle formulation of the present application utilizes amphiphilic block copolymers, typically diblock copolymers (i.e., one block is a hydrophobic polymer and the other block is a hydrophilic polymer). Compared with traditional low molecular weight surfactants, the hydrophobic block of the diblock copolymer can have a higher molecular weight, stronger hydrophobicity and higher rigidity (e.g., a higher glass transition temperature). Therefore, the critical micelle concentration of the polymer micelle of the present application is lower, and the drug loading capacity can be higher. Other amphiphilic block copolymers, such as triblock copolymers (e.g., two blocks are hydrophobic polymers and the other block is a hydrophilic polymer), can also be used and have similar characteristics.

[0075] Block copolymers of polyethylene glycol or methoxypolyethylene glycol with biodegradable polyesters such as polylactide, polyglycolide, poly(ε-caprolactone), and their copolymers can form micelles. Using higher molecular weight polylactide or other polyesters can achieve a long-lasting, sustained-release effect because longer polyester chains increase hydrophobic association and resist dissociation in the presence of blood components. However, the insoluble nature of longer polymer chains poses challenges in formulation and production. To produce micellar formulations, the copolymer and drug are typically dissolved in an organic solvent such as acetonitrile and acetone and then mixed with an aqueous solution. Upon solvent evaporation, micelles and even nanoparticles (in the case of longer polyester chains) can form, resulting in a drug-loaded polymer colloid in water. Drug crystallization often occurs during solvent evaporation, necessitating delicate processing, which often makes it uneconomical. Another approach is to use water-insoluble dichloromethane (DCM) to mitigate drug precipitation in the presence of water-soluble acetone and acetonitrile. However, DCM is more toxic and less popular. Since polyesters hydrolyze in the presence of water, in order to obtain long-term stability, the formulations need to be stored in frozen liquid or lyophilized form. Unfortunately, these micelles are very prone to aggregation and phase separation after freezing and lyophilization. Therefore, the cryoprotectants and lyoprotectants used in freezing and lyophilization and the process conditions need to be carefully studied (Abdelwahed W et al., 2006, Adv. Drug Delivery Reviews, 58, 1688-1713; Fonte P et al., 2016, J Contr. Rel., 225, 75-86).

[0076] In one aspect, the present application generally relates to a pharmaceutical composition of cinacalcet, comprising micelles containing cinacalcet or a pharmaceutically acceptable salt thereof, and at least one amphiphilic block copolymer.

[0077] In one or more embodiments, the amphiphilic block copolymer is a diblock copolymer.In one or more embodiments, the amphiphilic block copolymer is a biodegradable polyester-block-methoxypolyethylene glycol (MePEG).

[0078] In one or more embodiments, the amphiphilic block copolymer is a triblock copolymer.In one or more embodiments, the amphiphilic block copolymer is a biodegradable polyester-block-polyethylene glycol (PEG)-block-polyester.

[0079] In one or more embodiments, the polyester block is selected from the group consisting of poly(D,L-lactide), poly(L-lactide), poly(D-lactide), polyglycolide, poly(ε-caprolactone), and copolymers and mixtures thereof. In one or more embodiments, the polyester block is poly(D,L-lactide) (PDLLA). In one or more embodiments, the molecular weight (M) of PDLLA is n) is in the range of about 750 to about 50,000 (e.g., about 1,000 to about 30,000, about 1,300 to about 30,000, about 1,000 to about 20,000, about 1,300 to about 20,000).

[0080] In one or more embodiments, the molecular weight of MePEG is in the range of about 750 to about 20,000 (eg, about 1,200 to about 10,000, about 1,300 to about 6,000, about 1,900 to about 5,000).

[0081] In one or more embodiments, the molecular weight of PEG is in the range of about 200 to about 20,000 (eg, about 750 to about 20,000, about 1,200 to about 10,000, about 1,300 to about 6,000).

[0082] The pharmaceutical compositions of the present application may use any suitable form of cinacalcet, such as cinacalcet hydrochloride. Acceptable cinacalcet salts may be derived from inorganic or organic acids, including but not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, methanesulfonate, and undecanoate.

[0083] In one or more embodiments, the loading of cinacalcet hydrochloride in the amphiphilic block copolymer is from about 1% to about 70%, for example, from about 5% to about 20%, from about 8% to about 12%.

[0084] In one or more embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, carriers, or diluents.

[0085] In one or more embodiments, the one or more pharmaceutically acceptable excipients, carriers, or diluents are selected from a buffer, an osmotic pressure regulator, a cryoprotectant, a lyoprotectant or bulking agent, a surfactant, and a solvent.

[0086] In one or more embodiments, the pharmaceutical composition comprises one or more cryopreservative and lyoprotectants or bulking agents selected from the group consisting of mannitol, sucrose, trehalose, cyclodextrin, and derivatives thereof.

[0087] In one or more embodiments, the pharmaceutical composition comprises α-CD, β-CD, γ-CD hydroxypropyl-β-cyclodextrin (HPβCD), and / or sulfobutyl ether-β-cyclodextrin (SBEβCD).

[0088] In one or more embodiments, the pharmaceutical composition comprises HP[beta]CD at a concentration ranging from about 3% to about 10%, such as about 4% to about 8%, about 5% to about 7% (wt / v %).

[0089] It should be noted that where concentration is defined by weight / volume percentage (wt / v%), such concentration refers to an embodiment of the present application wherein the composition is a liquid (e.g., aqueous) composition comprising one or more solvents. In all other cases, concentration (%) refers to the weight percentage of the component in the composition.

[0090] In one or more embodiments, the pharmaceutical composition comprises a surfactant selected from polysorbates and poloxamers. In one or more embodiments, the polysorbates and poloxamers are selected from polysorbate 20, polysorbate 80, and Pluronic F68. In one or more embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration in the range of about 0.01% to about 0.5%, such as about 0.05% to about 0.5%, about 0.1% to about 0.5%, about 0.01% to about 0.1% (wt / v%).

[0091] In one or more embodiments, the pharmaceutical composition comprises a buffer. In one or more embodiments, the buffer is selected from acetate, citrate, and phosphate. In one or more embodiments, the pharmaceutical composition comprises acetic acid / sodium acetate or citric acid / sodium citrate, and the pH is in the range of about 4.0 to about 7.9 (e.g., about 4.0 to about 6.0, about 6.0 to about 7.0, about 7.0 to about 7.9).

[0092] In one or more embodiments, the pharmaceutical composition is an aqueous colloid. In one or more embodiments, the pharmaceutical composition is a transparent to translucent colloid. In one or more embodiments, the average particle size of the polymer micelles of the pharmaceutical composition is less than about 200 nm (e.g., less than about 175 nm, less than about 150 nm, less than about 50 nm).

[0093] In one or more embodiments, the pharmaceutical composition is in the form of a solution in an organic solvent. In one or more embodiments, the pharmaceutical composition is in the form of an aqueous liquid that can be stored frozen. In one or more embodiments, the pharmaceutical composition is in the form of a matrix. In one or more embodiments, the pharmaceutical composition is in a lyophilized form.

[0094] In one or more embodiments, the pharmaceutical composition is suitable for reconstitution and administration of cinacalcet.

[0095] In another aspect, the present application generally relates to a unit dosage form comprising the pharmaceutical composition.

[0096] In one or more embodiments, the unit dosage form is suitable for intravenous administration. In one or more embodiments, the unit dosage form is suitable for intraperitoneal administration.

[0097] In yet another aspect, the present application generally relates to a method for controlling PTH levels, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0098] In yet another aspect, the present application generally relates to a method for regulating calcium and phosphorus in the blood, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0099] In yet another aspect, the present application generally relates to a method for treating primary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0100] In yet another aspect, the present application generally relates to a method for treating secondary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0101] In yet another aspect, the present application generally relates to a method for treating parathyroid cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0102] In one or more embodiments of the method, the administration is intravenous administration. In one or more embodiments of the method, the administration is intraperitoneal administration. In one or more embodiments of the method, the administration is performed immediately before, during, or after the dialysis procedure of the experimenter. In one or more embodiments of the method, the administration is performed during the dialysis procedure of the experimenter.

[0103] In one or more embodiments of the method, administration of the pharmaceutical composition provides sustained release of cinacalcet.

[0104] In one or more embodiments of the methods, administration of the pharmaceutical composition does not induce phlebitis.

[0105] In another aspect, the present application generally relates to a method for preparing a composition of polymeric micelle cinacalcet disclosed herein, comprising: dissolving at least one amphiphilic block copolymer and cinacalcet or a pharmaceutically acceptable salt thereof in an organic solvent to form a first mixture; forming cinacalcet polymer micelles by one of methods A, B, or C; A: adding the first mixture to water or an aqueous solution while stirring to produce transparent to translucent colloidal cinacalcet micelles; B: adding the first mixture to water or an aqueous solution while stirring; removing the organic solvent to produce transparent to translucent colloidal cinacalcet micelles; C: removing the organic solvent and then adding an aqueous buffer to produce transparent to translucent colloidal cinacalcet micelles; and optionally adding one or more pharmaceutically acceptable excipients, carriers, or diluents. The aqueous micellar solution can be stored frozen or lyophilized for long-term storage.

[0106] In one or more embodiments of the preparation method, the organic solvent is selected from ethanol, acetone, acetonitrile, dichloromethane (DCM), isopropanol, ethyl acetate, tert-butanol, and methanol.

[0107] In one or more embodiments of the preparation method, the organic solvent is removed by evaporation.

[0108] In one or more embodiments of the preparation method, the amphiphilic block copolymer is a diblock copolymer.

[0109] In one or more embodiments of the preparation method, the amphiphilic block copolymer is biodegradable polyester-block-methoxypolyethylene glycol (MePEG).

[0110] In one or more embodiments of the preparation method, the amphiphilic block copolymer is a triblock copolymer.

[0111] In one or more embodiments of the preparation method, the amphiphilic block copolymer is a biodegradable polyester-block-polyethylene glycol (PEG)-block-polyester.

[0112] In one or more embodiments of the preparation method, the polyester block is selected from poly(D,L-lactide), poly(L-lactide), poly(D-lactide), polyglycolide, poly(ε-caprolactone), and copolymers and mixtures thereof.

[0113] In one or more embodiments of the preparation method, the polyester block is poly(D,L-lactide) (PDLLA).

[0114] In one or more embodiments of the preparation method, the one or more pharmaceutically acceptable excipients, carriers or diluents are selected from the group consisting of buffers, osmotic pressure regulators, cryopreservatives, lyoprotectants, fillers, surfactants and solvents.

[0115] In one or more embodiments of the preparation method, the molecular weight of PDLLA is in the range of about 750 to about 50,000.

[0116] In one or more embodiments of the preparation method, the molecular weight of MePEG is in the range of about 750 to about 20,000.

[0117] In one or more embodiments of the preparation method, the molecular weight of PEG is in the range of about 200 to about 20,000.

[0118] In one or more embodiments of the preparation method, the preparation method further comprises storing the frozen polymeric micellar cinacalcet at about -20°C for long-term storage.

[0119] In one or more embodiments of the preparation method, the preparation method further comprises storing the lyophilized polymeric micellar cinacalcet at about 2° C. to about 8° C. for long-term storage.

[0120] In one or more embodiments of the preparation method, the preparation method further comprises storing the cinacalcet polymer ethanol solution, cinacalcet / polymer matrix, or lyophilized polymer micellar cinacalcet at about 2° C. to about 8° C. for long-term storage.

[0121] In one or more embodiments of the preparation method, the preparation method further comprises reconstituting the lyophilized polymer micelle cinacalcet before administration.

[0122] In one or more embodiments of the preparation method, the preparation method further comprises reconstituting the cinacalcet polymer ethanol solution, cinacalcet / polymer matrix or lyophilized polymer micellar cinacalcet before administration.

[0123] An exemplary method for preparing a polymeric micellar cinacalcet composition involves dissolving cinacalcet hydrochloride and a diblock copolymer in a biocompatible solvent, such as ethanol. This is then diluted in an aqueous solution to produce a cinacalcet micellar formulation. Alternatively, the solvent can be removed, leaving the cinacalcet / polymer matrix to enhance stability. In the case of solvent removal, various solvents, such as acetone, acetonitrile, and DCM, can be selected, as they are ultimately removed, thereby mitigating safety concerns. The cinacalcet / polymer matrix can be dissolved in an aqueous solution and then lyophilized for faster reconstitution. This method is particularly suitable for water-soluble diblock copolymers.

[0124] Another exemplary method for preparing a polymeric micellar cinacalcet composition is to dissolve cinacalcet and a copolymer in an organic solvent, such as acetone, and then mix the resulting solution with an aqueous buffer solution. The solvent is removed by evaporation. After evaporation of the solvent, micelles or even nanoparticle formulations can be obtained. Cryoprotectants and / or lyoprotectants are added to prevent aggregation and phase separation of the micellar formulation after freezing and lyophilization. Surfactants can be added to further reduce the chance of aggregation. The micellar formulation is lyophilized to achieve long-term storage stability. The lyophilized formulation forms micellar cinacalcet upon reconstitution with an aqueous solution or water.

[0125] In yet another aspect, the present application generally relates to the use of the pharmaceutical compositions disclosed herein for controlling PTH levels.

[0126] In yet another aspect, the present application generally relates to the use of the pharmaceutical compositions disclosed herein for regulating calcium and phosphorus in the blood.

[0127] In yet another aspect, the present application generally relates to the use of the pharmaceutical compositions disclosed herein for treating primary hyperparathyroidism.

[0128] In yet another aspect, the application generally relates to the use of the pharmaceutical compositions disclosed herein for treating secondary hyperparathyroidism (eg, in patients with chronic kidney disease receiving dialysis).

[0129] In yet another aspect, the application generally relates to the use of the pharmaceutical compositions disclosed herein for treating hypercalcemia (eg, in patients with parathyroid cancer).

[0130] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in controlling parathyroid hormone (PTH) levels.

[0131] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in regulating calcium and phosphorus in the blood.

[0132] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating primary hyperparathyroidism.

[0133] In yet another aspect, the present application generally relates to the pharmaceutical compositions disclosed herein for use in treating secondary hyperparathyroidism.

[0134] In another aspect, the present application generally relates to a pharmaceutical composition disclosed herein for treating parathyroid cancer. In another aspect, the present application generally relates to a use of cinacalcet or a pharmaceutically acceptable salt thereof and at least one amphiphilic block copolymer in the preparation of a medicament.

[0135] In one or more embodiments, the medicament is used to control parathyroid hormone (PTH) levels.

[0136] In one or more embodiments, the medicament is used to regulate calcium and phosphorus in the blood.

[0137] In one or more embodiments, the medicament is for treating primary hyperparathyroidism.

[0138] In one or more embodiments, the medicament is for treating secondary hyperparathyroidism.

[0139] In one or more embodiments, the medicament is for treating parathyroid cancer.

[0140] Those skilled in the art will recognize that if there is a stereocenter in the compounds described herein, the stereoisomers and all optical isomers (e.g., R and S enantiomers) of the compound, together with the racemization of such isomers, diastereomers and other mixtures fall within the scope of the present application. When a compound as a single enantiomer or diastereomer is needed, it can be obtained by stereospecific synthesis or by the splitting of the final product or any appropriate intermediate. The splitting of the final product, intermediate or starting material can be achieved by any suitable method known in the art. For example, see " Stereochemistry of Organic Compounds " (Wiley-Interscience, 1994) by E.L. Eliel, S.H. Wilen and L.N. Mander.

[0141] According to the present invention, isomeric mixtures comprising any number of isomeric ratios can be employed. For example, when only two isomers are combined, the present invention contemplates mixtures comprising isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. It will be readily understood by those skilled in the art that similar ratios are contemplated for more complex isomeric mixtures.

[0142] Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compound" refers to a compound disclosed herein, including pharmaceutically acceptable salts and prodrugs thereof, each as described herein, wherein one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0143] By isotopically labeling the compounds disclosed herein, the compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 Compounds labeled with deuterium (C) are particularly preferred because of their ease of preparation and detectability. 2 H) substitution may be preferred in some cases due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, thereby providing certain therapeutic advantages. Isotopically labeled compounds disclosed herein, including pharmaceutically acceptable salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[0144] In addition, heavier isotopes such as deuterium are substituted for the normally abundant hydrogen ( 1 H) Certain therapeutic advantages may be achieved, for example, by improving absorption, distribution, metabolism and / or excretion (ADME) properties, leading to the development of drugs with improved efficacy, safety and / or tolerability. 13 C replaces the usually abundant 12 C may also produce beneficial effects. (See WO2007 / 005643, WO2007 / 005644, WO2007 / 016361 and WO2007 / 016431.)

[0145] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions having a content by weight equal to or greater than 95% ("substantially pure") and then used or formulated as described herein. In one or more embodiments, the purity of the compounds of the present invention is not less than 98%.

[0146] Solvates and polymorphs of the compounds of the present invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0147] The compositions of the present application may also contain adjuvants, such as preservatives. Protection against the action of microorganisms may be ensured by the addition of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be necessary to add isotonic agents, such as sugars, sodium chloride, and the like.

[0148] Any suitable delivery method can be used to administer the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof to mammals. The most suitable mode of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the therapy being used, as well as the nature of the active compound.

[0149] Useful dosages of the compounds described herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; for example, see U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0150] The amount of the compound described herein required for treatment may vary not only with the specific salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and may ultimately be determined at the discretion of the attending physician or clinician. In general, the total daily dose of the composition of the present application to a human or other mammalian host may be, for example, from about 0.05 mg / kg to about 8 mg / kg body weight (e.g., from about 0.1 mg / kg to about 8 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, from about 0.1 mg / kg to about 2 mg / kg) in single or divided doses.

[0151] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient, suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0152] The disclosed methods may include a kit comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, and explanatory materials describing the administration of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition to a subject. This should be understood to include other kit embodiments known to those skilled in the art, such as a kit comprising a (e.g., sterile) solvent for dissolving or suspending a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition prior to administration to a cell or subject. In some embodiments, the subject may be human.

[0153] The materials, compositions, and components disclosed herein can be used in the disclosed methods and compositions, can be used in conjunction with the disclosed methods and compositions, can be used to prepare the disclosed methods and compositions, or can be products of the disclosed methods and compositions. It should be understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, even if each individual and collective combination and permutation of these compounds is not explicitly mentioned, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed, and various modifications that can be made to several molecules included in the method are discussed, unless specifically stated to the contrary, every combination and permutation of the method and possible modifications are specifically contemplated. Similarly, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of the present disclosure, including but not limited to the method steps using the disclosed formulations. Therefore, if there are various additional steps that can be performed, it should be understood that these additional steps can be performed with any specific method step or combination of steps of the disclosed method, and each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0154] Example

[0155] The following examples are given for the purpose of illustrating the present application but not to limit the scope or spirit of the present application.

[0156] Biodegradable polyester-block-MePEG diblock copolymers (e.g., PDLLA- MePEG) and polyester-block-PEG-block-polyester triblock copolymers (e.g., PDLLA-PEG-PDLLA)

[0157] Biodegradable polyester-block-methoxypolyethylene glycol (MePEG) diblock copolymers or polyester-block-PEG-block-polyester triblock copolymers are synthesized by ring-opening polymerization of monomers such as D,L-lactide, D-lactide, L-lactide, glycolide, and ε-caprolactone in the presence of MePEG or PEG and stannous octoate. The hydroxyl groups of MePEG or PEG act as initiators for the ring-opening polymerization, thereby attaching to the growing polyester chain to form polyester-MePEG diblock or polyester-PEG-polyester triblock copolymers. Stannous octoate serves as a catalyst. Monomers or a mixture thereof, MePEG or PEG of varying molecular weights, and stannous octoate are added to a clean flask while stirring. The flask is sealed and heated to 120°C to 160°C while stirring to carry out bulk melt polymerization. Polymerization is typically complete within 72 hours. Impurities in the monomers can be removed by recrystallization before polymerization. Water can be removed from the MePEG or PEG by vacuum treatment.

[0158] The type of monomer, molecular weight of MePEG or PEG, and ratio of monomer to MePEG or PEG can be adjusted depending on the desired polymer composition and properties. The expected molecular weight of the polyester block can be calculated as follows: weight ratio of monomer to MePEG x molecular weight of MePEG, or weight ratio of monomer to PEG 1 / 2 x molecular weight of PEG.

[0159] Example 1a.

[0160] To a clean 250 mL flask equipped with a magnetic stirrer, add 75 g of D,L-lactide (DLLA), 25 g of MePEG (molecular weight 5,000), and 0.2 g of stannous octoate. The flask is sealed and immersed in an oil bath heated to 135°C. The contents are stirred for approximately 8 hours while maintaining the temperature at 125-150°C. The polymerization reaction is quenched by cooling to room temperature to yield a diblock copolymer.

[0161] Example 1b.

[0162] To a clean 10 mL flask equipped with a magnetic stirrer, add 6 g of PEG (molecular weight 3,350). Immerse the flask in a metal sand bath heated to approximately 140°C to melt the PEG. While stirring, apply vacuum for 2 hours to remove any residual moisture from the PEG. Then, add 4 g of D,L-lactide. Once melted, add 0.03 g of stannous octoate. After each opening of the flask, briefly apply vacuum to remove moisture, then seal the flask. Maintaining the temperature at approximately 140°C, stir the contents for approximately 17 hours. Quench the polymerization reaction by cooling to room temperature to produce a triblock copolymer.

[0163] The polymer in Example 1a is designated PDLLA-MePEG 15-5, representing a diblock of poly(D,L-lactide) (PDLLA) and MePEG, and its expected molecular weight, wherein the PDLLA block is 15k and the MePEG block is 5k. The polymer in Example 1b is designated PDLLA-PEG-PDLLA 1.1-3.35-1.1, representing a triblock of poly(D,L-lactide) (PDLLA) and PEG, and its expected molecular weight, wherein the PDLLA block is 1.1k and the PEG block is 3.35k. Table 1 provides examples of various block polymers synthesized by this method. Table 2 provides additional examples of various block polymers synthesized, and their molecular weight, molecular weight distribution, and oligomer content are respectively calculated by 1 H-NMR, GPC and RP-HPLC determination. Example GPC chromatogram is as follows Figure 2 shown.

[0164] Table 1. Diblock and triblock copolymers and their properties

[0165]

[0166]

[0167] Table 2. Molecular weight and polydispersity of synthesized PLA-MePEG diblock copolymers and PLA-PEG-PLA triblock copolymers

[0168]

[0169] a :pass 1 H-NMR confirmed that, in addition to the triblock copolymer

[0170] b : Polydispersity is the ratio of weight average molecular weight to number average molecular weight determined by GPC using THF as mobile phase and PEG as standard

[0171] c : Determined by RP-HPLC

[0172] d : Number average molecular weight was determined by GPC using THF as mobile phase and PEG as standard

[0173] Preparation of block copolymer cinacalcet solution (method A) or matrix (method C) for micelle formation and lyophilization

[0174] The polymeric micellar cinacalcet formulation can be prepared by dissolving cinacalcet hydrochloride and the block copolymer in a biocompatible solvent, followed by dilution in an aqueous solution (eg, saline or water).

[0175] Example 2 (Table 3, Formulation L).

[0176] 2.4 g of PDLLA-MePEG 5-5 was added to 5.6 mL of ethanol and heated to 40-50°C to obtain a polymer solution. 0.27 g of cinacalcet hydrochloride was then added to the polymer solution to obtain a cinacalcet / polymer ethanol solution. The polymer solution was diluted 1:10 with normal saline to obtain a colloidal solution. The turbidity after 15-fold dilution was 42.5 NTU.

[0177] Example 3 (Table 3, Formulation I).

[0178] Add 3.4 g of PDLLA-MePEG 1.3-1.9 to 7.9 mL of ethanol and warm to approximately 50°C to obtain a polymer solution. Then, add 0.42 g of cinacalcet hydrochloride to the polymer solution to obtain a cinacalcet / polymer ethanol solution. Dilute the polymer solution with saline at a ratio of 1:10 to obtain a clear solution.

[0179] Tables 3, 4a, and 4b provide compositions evaluated using the above method. Note that the organic solvent, ethanol, can be removed from the formulation to yield a cinacalcet / copolymer matrix, thereby improving long-term storage stability. The cinacalcet / polymer matrix can be dissolved in an aqueous solution and lyophilized for rapid reconstitution. Table 5 provides an exemplary formulation prepared by lyophilization. This method is particularly suitable for water-soluble diblock copolymers. Figure 3 A typical example of the particle size distribution of cinacalcet polymer micelles measured by DLS is provided.

[0180] Table 3. Preparation Methods for Evaluated Polymeric Micellar Cinacalcet Formulations—Cinacalcet HCl and block copolymers were dissolved in a biocompatible solvent and then diluted with water or saline.

[0181]

[0182] Table 4a. Cinacalcet polymer micelle-ethanol solution formulation (Cinacalcet hydrochloride and block copolymer were dissolved in ethanol and then diluted with water)

[0183]

[0184] a : Concentration of Cinacalcet in ethanol

[0185] b :Contains about 20mg / mL of NaOAc

[0186] Table 4b. Cinacalcet polymer micelle-ethanol solution formulation (Cinacalcet hydrochloride and block copolymer were dissolved in ethanol and then diluted with D5W)

[0187]

[0188]

[0189] a : Concentration of Cinacalcet in ethanol

[0190] b :Contains about 20mg / mL of NaOAc

[0191] Table 5. Cinacalcet Polymer Micelles - Lyophilized b Formulation (Cinacalcet HCl and block copolymers were dissolved in tert-butyl alcohol or ethanol, the ethanol was removed, diluted in an aqueous solution, and lyophilized to remove water or alcohol)

[0192]

[0193]

[0194] a Prepare a cinacalcet / polymer / ethanol solution ((cinacalcet + polymer):ethanol = 1:2 w / v). Remove the ethanol using vacuum and mild heating (approximately 45°C). Reconstitute the cinacalcet / polymer matrix with diluent to a cinacalcet concentration of 10 mg / mL, or 5 mg / mL for NB009-160-MT. For a cinacalcet / polymer / tert-butyl alcohol solution ((cinacalcet + polymer):tert-butyl alcohol = 1:4 w / v), add the diluent directly to prepare a 10 mg / mL cinacalcet solution.

[0195] b : 2 mL of the above reconstituted cinacalcet solution was added to a glass vial and lyophilized to remove moisture.

[0196] c : Add 1.85 mL of water to the lyophilized formulation to obtain a reconstituted cinacalcet solution with a concentration of 5 mg / mL or 10 mg / mL.

[0197] d The reconstituted 10 mg / mL cinacalcet solution was diluted 5-fold with NS or D5W, and the turbidity and pH were measured.

[0198] Preparation of Cinacalcet Micelles (Method B) and Lyophilization

[0199] Cinacalcet polymer micelles can also be prepared by dissolving both cinacalcet hydrochloride and the copolymer in an organic solvent (such as acetone, acetonitrile, and DCM), mixing with water, and then removing the organic solvent. This method is particularly suitable for water-insoluble copolymers. Acetone is a preferred solvent because of its low toxicity, high solubility for both cinacalcet hydrochloride and the copolymer, and high volatility. However, during solvent evaporation, cinacalcet hydrochloride tends to form crystals. Therefore, it is necessary to develop optimal formulations and process conditions for easy production.

[0200] Table 6 provides the compositions and methods evaluated during the screening process. Note that formulations with higher drug loading and drug concentration (e.g., 10% or higher drug loading and 5 mg / mL cinacalcet concentration) are preferred. PLA and PLGA are preferred over PCL due to their proven biocompatibility. None of the formulations studied in Table 6 achieved a 10% drug loading and 5 mg / mL concentration unless PCL was used as a hydrophobic block. Presumably, the greater hydrophobicity of PCL may contribute to the increased drug payload and concentration.

[0201] Table 6. Preparation of Evaluated Polymeric Micellar Cinacalcet Formulations—Cinacalcet HCl and diblock copolymer dissolved in solvent, mixed with aqueous solution, and then the solvent removed by evaporation

[0202]

[0203]

[0204] To achieve the desired drug loading and concentration, we found that acetate buffer helped prevent crystallization of cinacalcet hydrochloride during solvent evaporation. The presence of cyclodextrins, such as hydroxypropyl β-cyclodextrin (HPβCD), further enhanced drug loading.

[0205] Table 7 provides further investigated formulations with drug loadings up to 10% and up to 5 mg / mL or higher. The investigated compositions and preparation methods also demonstrated robustness.

[0206] Based on the results in Table 7, the following observations were made. Sodium acetate (NaOAc) buffer at concentrations of 80-100 mM better prevented drug crystallization during acetone evaporation. PDLLA-MePEG exhibited higher drug loading capacity than PLGA-MePEG, likely due to its higher hydrophobicity. The addition of HPβCD also enhanced drug loading capacity. The addition of small amounts of surfactants, such as polysorbate 80 (PS 80) and Pluronic F68, inhibited potential aggregation.

[0207] Example 4 (Table 7, Formulation BM).

[0208] 2 mL of 100 mM sodium acetate, 2 mL of 300 mg / mL HPβCD, and 6 mL of water were mixed to form an aqueous solution. 3.3 mL of 30 mg / mL cinacalcet hydrochloride in acetone and 2 mL of 200 mg / mL PDLLA-MePEG 20-5 in acetone were mixed to form an organic solution. The aqueous and organic solutions were combined to form a clear solution, which was stirred for 20 hours to allow the acetone to evaporate. The solution was then brought to volume (QS) with water to 10 mL. This yielded a colloidal solution with a drug loading of 20%, a drug concentration of 10 mg / mL, and a pH of 4.5.

[0209] Example 5 (Table 7 Formulations DO).

[0210] 0.56 g of cinacalcet hydrochloride, 5.01 g of PDLLA-MePEG 15-5, and 70 mL of acetone were combined to form an organic solution. While magnetically stirring (approximately 400-500 rpm), this solution was added to 100 mL of a 0.1 M NaOAc solution in 0.01% PS80 (pH 7.9). The acetone evaporated over approximately 20 hours, yielding a colloidal preparation with a total weight of 85.5 g (minor water evaporation also occurred). 6 g of HPβCD was then added to the colloidal preparation, and the volume was adjusted to 100 mL with water.

[0211] Example 6 (Table 7 Formulation DW).

[0212] An organic solution was prepared by combining 1.17 g of cinacalcet hydrochloride, 10 g of PDLLA-MePEG 15-5, and 120 mL of acetone. While magnetically stirring, this solution was added to 200 mL of 0.1 M aqueous NaOAc solution, pH 7.8. The acetone evaporated over approximately 36 hours, yielding 201 mL of a colloidal preparation with a pH of 5.1 and a turbidity of 12.3 NTU at a 1:15 dilution.

[0213] Table 7. Preparation of polymeric micellar cinacalcet formulations evaluated by solvent evaporation—the effects of buffer, low temperature, and lyoprotectants.

[0214]

[0215]

[0216]

[0217] Freeze-thaw stable cinacalcet polymer micelle formulation

[0218] The polyester in the diblock copolymer degrades by hydrolysis in the presence of water. To increase stability, the formulation can be stored frozen. The freeze-thaw stability of the polymer micelle cinacalcet formulation was evaluated (Table 8). In the absence of a protective agent, the polymer micelles aggregated after freeze-thaw. Sucrose and trehalose provided some protection against aggregation. HPβCD had the best protective effect. No significant aggregation was observed.

[0219] Table 8. Freeze-thaw stability of polymeric micellar cinacalcet formulations

[0220]

[0221]

[0222]

[0223] Freeze-dried stable PDLLA-MePEG cinacalcet micelle formulation

[0224] Formulations that are stable during lyophilization, especially for water-insoluble diblock copolymers (Table 1), are not easily achieved, yet lyophilized formulations are required to ensure long-term storage stability. We evaluated various excipients as lyoprotectants. Different excipients were added to Formulation DW (Example 6), lyophilized, and then reconstituted. Table 9 shows that 10% HPβCD effectively prevented aggregation of the cinacalcet-loaded polymer during lyophilization. A small amount of PS 80 surfactant further facilitated reconstitution.

[0225] Table 9. Evaluation of lyophilized stable formulations

[0226] preparation excipient Pie Appearance Reconstituted appearance DS 10% HPβCD White cake All dissolved, transparent colloid DU 10% HPβCD White cake All dissolved, transparent colloid DV 10% HPβCD + 0.1% PS80 White cake All dissolved, transparent colloid DW 10% HPβCD + 0.3% PS80 White cake All dissolved, transparent colloid DX 10% HPβCD + 0.5% PS80 White cake All dissolved, transparent colloid

[0227] Example 7 (Formulation DX).

[0228] 0.6 g of cinacalcet hydrochloride, 5 g of PDLLA-MePEG 15-5, and 60 mL of acetone were combined to obtain an organic solution. While magnetically stirring, the above solution was added to 100 mL of 0.1 M NaOAc aqueous solution at a pH of 7.8. The acetone and a small amount of water were evaporated to obtain 85 g of the colloidal preparation. 10 g of HPβCD and 1 mL of 10% PS80 were added to the resulting mixture and the volume was adjusted to 100 g (approximately 100 mL) with water. A transparent colloidal polymer micellar cinacalcet preparation was obtained. The pH was 5.2, and the turbidity at a 1:15 dilution was 10.7 NTU. 1 mL of the preparation was added to each 3 mL vial and lyophilized. The lyophilization cycle was as follows: Freezing: rate 5°F / min, -35°F for 2 hr, -5°F for 2 hr, -35°F for 3 hr; Drying: -35°F for 10 hr, 25°F for 8 hr, then 75°F for 8 hr, pressure below 200 mTorr.

[0229] A white cake is obtained. After redissolution with water or other aqueous solutions, a colloidal micelle solution (15-fold dilution turbidity = 12 NTU) is obtained.

[0230] Physical Evaluation of Cinacalcet Polymeric Micellar Formulations

[0231] The formulations were screened by testing the appearance, pH, turbidity, and UV-Vis absorbance of 15-fold diluted solutions. The release of cinacalcet from the polymer micelle formulations through a 12-14 kD dialysis membrane into 20 mM PBS buffer at 37°C, pH 7.4, containing 0.1% PS80 was determined ( Figure 4 The cinacalcet concentration in the PBS buffer was determined by UV absorbance at 282 nm. The results demonstrated sustained release of cinacalcet from the polymer micelle formulation. These results suggest that cinacalcet binds strongly to the diblock copolymer, potentially providing long-lasting circulation in the blood.

[0232] Cinacalcet unbound fractions

[0233] Determine the unbound portion of cinacalcet in plasma. Cinacalcet buffer solution and cinacalcet polymer micelles were mixed with rabbit plasma at a ratio of 1:4, incubated at 37°C, and filtered through a 30kD ultrafiltration membrane. The filtrate and unfiltered plasma were mixed with acetonitrile at a ratio of 1:4, and the cinacalcet concentration was determined by RP-HPLC. Table 10 presents the unbound (filtered) and total (unfiltered) cinacalcet concentrations, and the unbound fraction % (unbound concentration divided by total concentration) was calculated. As shown in Table 10, the unbound fraction of cinacalcet polymer micelles was 20+ times lower than that of cinacalcet buffer solution.

[0234] Table 10. Unbound and Total Cinacalcet Concentrations - Polymeric Micellar Formulations

[0235]

[0236]

[0237] a : Cinacalcet dissolved in 100 mM NaOAc / HOAc, pH 4.0, 1 mg / mL

[0238] b Lyophilized cinacalcet polymer micelles were reconstituted with water to a cinacalcet concentration of 10 mg / mL, and then diluted with D5W to 1 mg / mL

[0239] c : Mix with rabbit plasma at a ratio of 1:4 and incubate at 37°C for 5 or 15 minutes

[0240] Evaluation of the blood compatibility of cinacalcet polymer micelle formulations

[0241] Fresh blood from a human donor was diluted 13.5 times with 0.9% saline. 0.1 mL of 1 mg / mL cinacalcet formulation was added to 4.9 mL of diluted whole blood. The glass vial container was gently mixed for 0.5 hours. After the blood cells settled, the color of the supernatant was observed ( Figure 5a ). As shown, the supernatants of the free cinacalcet solution and the micelle formulations with 30%-70% cinacalcet loading were reddish, with free cinacalcet being the reddest. The reddish color originates from cell lysis, indicating blood incompatibility. In contrast, the polymeric micelles with 5%-10% cinacalcet loading had the same non-reddish color as the saline negative control, indicating that these formulations were compatible with blood cells. The polymeric micelle formulations effectively encapsulated cinacalcet and improved the blood compatibility of cinacalcet. Interestingly, using acetate buffer at pH 6.2 improved blood compatibility (compare formulations AL and AN) with the same polymer and the same drug loading and concentration.

[0242] Another study compared cinacalcet buffer solution (100 mM NaOAc / HOAc, pH 4.0) and a cinacalcet polymer micelle formulation. A test tube was filled with 2.5 mL of 2% rabbit red blood cells, 2.2 mL of NS, and 0.3 mL of cinacalcet sample. Normal saline (NS) and water were used as negative and positive controls, respectively. The tube was gently mixed and incubated at 37°C. The supernatant was centrifuged and the absorbance (A) at 540 nm was measured. The percentage of hemolysis was calculated as follows:

[0243] Hemolysis (%) = (A 样品 –A 阴性对照 ) / (A 阳性对照 –A 阴性对照 )

[0244] The results in Table 11 show that the polymeric micelle formulation significantly reduced hemolysis compared to the cinacalcet buffer solution. Figure 5b Exemplary photographs of hemolysis test results are provided.

[0245] Table 11. Comparison of hemolysis between Cinacalcet-polymer micelle formulation and simple solution

[0246]

[0247] Evaluation of the Stability of Cinacalcet Polymeric Micellar Formulations

[0248] Liquid or lyophilized polymer micelle cinacalcet formulations were stored at -20°C, 2-8°C, room temperature and 40°C for stability observation. The physical appearance (before and after reconstitution of the lyophilized samples), turbidity (15-fold dilution NTU), pH and UV absorbance were monitored at different storage times. At room temperature and 40°C, the appearance (especially aggregation), turbidity and pH (pH reduction due to polyester hydrolysis) of the liquid and lyophilized samples showed significant changes in a short period of time. On the other hand, the selected liquid formulations achieved long-term storage stability at -20°C, and the selected lyophilized formulations achieved long-term storage stability at 2-8°C. No significant changes were observed in the test parameters. Figure 6 and Figure 7 It was shown that the most sensitive parameter - turbidity - remained stable during the storage period.

[0249] Additional storage stability data for lyophilized cinacalcet polymer micelles are provided in Table 12. Tables 13a and 13b illustrate the stability of lyophilized and ethanolic solution formulations after reconstitution, respectively.

[0250] Table 12. Stability of lyophilized cinacalcet polymer micelle formulations (batch NB009-030) stored at 2-8°C.

[0251]

[0252] Table 13a. Stability of reconstituted lyophilized cinacalcet polymer micelle formulation (batch NB009-030)

[0253]

[0254]

[0255] ND = Not Detected

[0256] a : Reconstitute NB009-030 in 1.85 ml of water and store at 4°C or 25°C, respectively.

[0257] Table 13b. Stability of reconstituted Cinacalcet ethanol solution polymer micelle formulation (ID SP-240708)a

[0258]

[0259] a: Dilute 10 times with water or D5W; store the sample at room temperature of approximately 25°C

[0260] In vivo evaluation of cinacalcet polymer micelle formulation

[0261] In four independent studies, the overall safety, injection site reactions, pharmacokinetics, and efficacy (PTH reduction) of cinacalcet polymeric micelles were evaluated at different doses in healthy adult male Sprague Dowley (SD) rats. A buffered cinacalcet solution was used for comparison. Normal saline and polymeric micelle carriers were also tested.

[0262] Rat Study 1

[0263] Healthy adult male Sprague-Dawley rats were divided into four groups of six rats each. On days 1, 3, 5, and 8, normal saline (NS), two cinacalcet polymer micelles (lots NB007-010A and NB007-013), and 3 mg / kg cinacalcet in cinacalcet buffer (lot NB007-017) were administered via the tail vein. General health was observed and body weight was recorded. Blood samples were collected by tail tip snip at 0, 1, 4, 8, and 24 hours after each dose. Plasma PTH levels were measured using an ELISA kit.

[0264] During drug administration, all rats in the cinacalcet buffered solution group and some rats in the cinacalcet polymer micelle group developed black tails due to drug stimulation. The NS negative control group did not develop black tails. Therefore, blood samples could not be collected from some rats that developed black tails. Table 14 provides a summary of the number of rats that developed black tails. Table 15 presents body weights, with the negative control group showing the greatest increase and the cinacalcet buffered solution group showing the least increase. Figure 8A reduction in PTH levels was shown in Figure 2. Similar reductions were observed in the cinacalcet buffer solution and cinacalcet polymer micelle groups.

[0265] The results showed that the polymeric micelles improved safety, reduced irritation and phlebitis (black tail), and effectively reduced PTH levels.

[0266] Table 14. Number of blood samples collected by tail snip in adult male SD rats following intravenous administration of normal saline and 3 mg / kg cinacalcet. Blood was not collected due to the appearance of a black tail after cinacalcet administration (rat study 1).

[0267]

[0268] a : Blood was collected by tail snip at 0, 1, 4, 8, and 24 hours after each administration.

[0269] b : 5 mg / mL Cinacalcet, 45 mg / mL PDLLA-MePEG 15-5, 50 mg / mL HPβCD, 1 mg / mL PS80, dissolved in 100 mM NaOAc buffer (NB007-017).

[0270] c : 5 mg / mL Cinacalcet, 49 mg / mL PDLLA-MePEG 2-2, 5% v / v ethanol, 5% w / v sucrose, dissolved in 100 mM NaOAc buffer (NB007-017).

[0271] d : 2 mg / mL Cinacalcet, 4% v / v ethanol, dissolved in 100 mM HOAc / NaOAc pH 4.0 buffer (NB007-017).

[0272] Table 15. Body weight of adult male SD rats after intravenous administration of NS and 3 mg / kg cinacalcet (rat study 1)

[0273] sky Negative control LS-001 LS-002 LS-003 1 311.0±10.3 300.2±12.0 301.3±3.6 304.0±8.5 3 324.2±13.2 308.2±13.7 313.0±5.4 304.2±12.2* 5 338.3±18.1 316.0±16.2* 326.7±8.0 301.5±13.3** 8 362.7±18.7 332.0±17.8* 343.2±10.4* 318.7±13.3***

[0274] Compared with the negative control group, *: P < 0.05. **: P < 0.01, ***: P < 0.001

[0275] Rat Study 2

[0276] Healthy adult male SD rats were divided into 6 groups of 4 rats each and injected with normal saline (NS), cinacalcet polymer micelles (cinacalcet dose: 2, 1, 0.5, 0.25 mg / kg; 10 mL / kg), and cinacalcet buffer solution (cinacalcet dose: 0.25 mg / kg; 10 mL / kg) via the tail vein on days 1, 3, 5, 8, 10, and 12. General health was observed and body weight was recorded. Blood samples were collected intraorbitally on days 1, 8, and 12. The sampling times on days 1 and 12 were 0, 1, 2, 4, 8, and 24 hours. The sampling times on day 8 were 0, 1, and 24 hours. The concentration of cinacalcet in plasma was measured by LC-MS.

[0277] No black tails were observed in any of the groups. The rats appeared generally healthy. Table 16 lists body weights, with the negative control group and the 0.25 mg / kg cinacalcet polymer micelle group showing the greatest weight gain. The remaining groups showed less weight gain. Figure 9 The plasma concentration of cinacalcet is shown in Figure 2. The AUC of the polymer micelle group was linearly correlated with the administered dose and showed that cinacalcet accumulated after repeated injections.

[0278] The results showed that the polymeric micelles were well tolerated, the pharmacokinetic curve showed a linear dose-response, and cinacalcet accumulated after repeated injections.

[0279] Table 16. Body weight of adult male SD rats after intravenous administration of cinacalcet (4 rats per group) a (Rat Study 2)

[0280]

[0281]

[0282] a : Injection was performed via tail vein on days 1, 3, 5, 8, 10, and 12; blood samples were collected via eye pocket on days 1, 8, and 12; collection time on days 1 and 12: 0, 1, 2, 4, 8, 24 hours; collection time on day 8: 0, 1, 24 hours; overall health, tail color, and body weight were observed; and cinacalcet concentration in plasma was measured by LC-MS.

[0283] b : LS-002 and LS-003 were diluted with normal saline to the corresponding cinacalcet concentrations.

[0284] c : 5 mg / mL Cinacalcet, 49 mg / mL PDLLA-MePEG 2-2, 5% v / v ethanol, 5% w / v sucrose, dissolved in 100 mM NaOAc buffer (NB007-017).

[0285] d : 2 mg / mL Cinacalcet, 4% v / v ethanol, dissolved in 100 mM HOAc / NaOAc pH 4.0 buffer (NB007-017).

[0286] Rat Study 3

[0287] Healthy adult male SD rats were divided into 3 groups, with 6 rats in each group. On days 1, 3, 5, 8, 10, and 12, cinacalcet buffer solution (cinacalcet dose: 2 mg / kg, 2 mL / kg), cinacalcet polymer micelles (cinacalcet dose: 2 mg / kg, 2 mL / kg), and polymer carrier (90 mg / kg, 2 mL / kg) were injected via the tail vein. Overall health and tail appearance were observed, and body weight was recorded. Blood samples were collected through the eye socket. Plasma was separated 5 minutes and 1 hour after collection and filtered through 30kD ultrafiltration microtubes to determine unbound cinacalcet. Cinacalcet concentration was determined by LC-MS.

[0288] Rats in the cinacalcet buffer solution group struggled during the injection, while the other two groups did not. Tail appearance was assessed using the scoring system listed in Table 17. Severe black tails and lesions were observed in the cinacalcet buffer solution group. Only minor reactions were observed in the cinacalcet polymer micelle group. No reactions were observed in the polymer vehicle group (Table 18). Figure 10 Body weights are provided, with the cinacalcet buffer group showing the smallest weight gain. Table 19 lists the cinacalcet concentrations in plasma (total and unbound). Unbound cinacalcet was below the limit of quantification, indicating extensive binding of cinacalcet to blood components. Similar total cinacalcet concentrations were observed between the cinacalcet buffer solution and the cinacalcet polymer micelles.

[0289] The results showed that cinacalcet polymer micelles significantly improved safety and were better tolerated than cinacalcet buffered solution by reducing injection site reactions.

[0290] Table 17. Tail appearance scores

[0291]

[0292] Table 18. Tail reaction scores after repeated intravenous injection of cinacalcet formulations (rat study 3)

[0293]

[0294] a : 1 mg / mL cinacalcet dissolved in 100 mM acetate buffer, pH 4.0

[0295] b : Lyophilized cinacalcet polymer micelles batch NB009-030 were reconstituted with water to a cinacalcet concentration of 10 mg / mL, and then diluted with D5W to a concentration of

[0296] c : 45 mg / mL polymer 009-029 dissolved in 100 mM NaOAc, dose 90 mg / kg

[0297] d Blood samples were collected via the eye socket at the following time points: Day 1: before administration; Day 3: 0 (before administration), 5 minutes, 1, 4, 8, 24, 48 hours; Day 5: 72 hours; Day 12: 0 (before administration), 5 minutes, 1, 4, 8, 24, 48, 72 hours

[0298] Table 19. Unbound and Total Cinacalcet Concentrations in Rat Plasma (Rat Study 3)

[0299]

[0300] a : There was one outlier at 1.81 ng / mL. LLOQ (Lower Limit of Quantitation) = 0.500 ng / mL.

[0301] Rat Study 4

[0302] Healthy adult male SD rats were divided into three groups, with six rats in each group. Cinacalcet buffer solution (cinacalcet dose: 2 mg / kg, 10 mL / kg), cinacalcet polymer micelles (cinacalcet dose: 2 mg / kg, 10 mL / kg), and 5% glucose (D5W, 10 mL / kg) were administered via the tail vein on days 1, 3, 5, 8, 10, and 12. Overall health and tail appearance were observed, and body weight and tail diameter were recorded.

[0303] Rats in the cinacalcet buffer solution group struggled during the injection, while the other two groups did not. Tail appearance was assessed using the scoring system listed in Table 17. Severe black tails appeared in the cinacalcet buffer solution group. Minor reactions were observed in the cinacalcet polymer micelle group. No reactions were observed in the D5W negative control group (Table 20). Figure 11 The diameter of the tail close to the body is presented, with the cinacalcet buffer solution group having the largest value. A larger diameter indicates inflammation or swelling caused by side effects.

[0304] The results again showed that cinacalcet polymer micelles had significantly improved safety and were better tolerated than cinacalcet buffer solution.

[0305] Table 20. Tail reaction scores after repeated intravenous injection of cinacalcet formulations (rat study 4)

[0306]

[0307] a : 1 mg / mL cinacalcet dissolved in 100 mM acetate buffer, pH 4.0

[0308] b : Lyophilized cinacalcet polymer micelles batch NB009-176 were reconstituted with water to a cinacalcet concentration of 10 mg / mL, and then diluted with D5W to a concentration of

[0309] c : 5% glucose water (D5W)

[0310] Industrial Applicability

[0311] The compositions of the present application are easy to produce, stable after freezing and lyophilization, and stable during long-term storage. These pharmaceutical compositions are hemocompatible and reduce phlebitis and pain after intravenous administration. The pharmaceutical formulations of the present application can be conveniently administered intravenously during dialysis and, compared to oral cinacalcet tablet formulations, improve patient compliance, increase bioavailability, and reduce variability in pharmacokinetic parameters, thereby eliminating the "food effect."

Claims

1. A pharmaceutical composition of cinacalcet, comprising micelles containing cinacalcet or a pharmaceutically acceptable salt thereof, and at least one amphiphilic block copolymer.

2. The pharmaceutical composition according to claim 1, wherein The amphiphilic block copolymer is a diblock or triblock copolymer.

3. The pharmaceutical composition according to claim 1 or 2, wherein The amphiphilic block copolymer is biodegradable polyester-block-methoxypolyethylene glycol (MePEG) or biodegradable polyester-block-polyethylene glycol (PEG)-block-polyester.

4. The pharmaceutical composition according to claim 3, wherein The polyester block is selected from poly (D, L-lactide), poly (L-lactide), poly (D-lactide), polyglycolide, poly (ε-caprolactone), and Copolymers or mixtures thereof.

5. The pharmaceutical composition according to claim 4, wherein The polyester block is poly(D,L-lactide) (PDLLA).

6. The pharmaceutical composition according to claim 5, wherein The molecular weight of PDLLA (M n ) is in the range of about 750 to about 50,000.

7. The pharmaceutical composition according to claim 6, wherein The molecular weight of PDLLA ranges from about 1,000 to about 30,000.

8. The pharmaceutical composition according to claim 7, wherein The molecular weight of PDLLA ranges from about 1,000 to about 20,000.

9. The pharmaceutical composition according to any one of claims 3 to 8, wherein The molecular weight of the MePEG and PEG ranges from about 750 to about 20,000.

10. The pharmaceutical composition according to claim 9, wherein The molecular weight of the MePEG and PEG ranges from about 1,300 to about 6,000.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein The loading amount of the cinacalcet hydrochloride in the amphiphilic block copolymer is about 1% to about 70%.

12. The pharmaceutical composition according to claim 11, wherein The loading amount of the cinacalcet hydrochloride in the amphiphilic block copolymer is about 5% to about 20%.

13. The pharmaceutical composition according to claim 12, wherein The loading amount of the cinacalcet hydrochloride in the amphiphilic block copolymer is about 8% to about 12%.

14. The pharmaceutical composition according to any one of claims 1 to 13, further comprising one or more pharmaceutically acceptable excipients, carriers or diluents.

15. The pharmaceutical composition according to claim 14, wherein The one or more pharmaceutically acceptable excipients, carriers or diluents are selected from buffers, osmotic pressure regulators, cryopreservatives, lyoprotectants, fillers, surfactants and solvents.

16. The pharmaceutical composition according to claim 15, comprising one or more cryopreservative and lyoprotectant or bulking agents selected from mannitol, sucrose, trehalose, cyclodextrin and derivatives thereof.

17. The pharmaceutical composition according to claim 16, comprising α-CD, β-CD, γ-CD hydroxypropyl-β-cyclodextrin (HPβCD) and / or sulfobutyl ether-β-cyclodextrin (SBEβCD).

18. The pharmaceutical composition according to claim 16 or 17, comprising HP[beta]CD at a concentration ranging from about 3% to about 10% (wt / v %).

19. The pharmaceutical composition according to any one of claims 15 to 18, comprising a surfactant selected from polysorbates and poloxamers.

20. The pharmaceutical composition according to claim 19, wherein The polysorbate and poloxamer are selected from polysorbate 20, polysorbate 80, and Pluronic F68.

21. The pharmaceutical composition of claim 19 or 20, comprising polysorbate 80 at a concentration in the range of about 0.01% to about 0.5% (wt / v %).

22. The pharmaceutical composition according to any one of claims 1 to 21, comprising a buffer.

23. The pharmaceutical composition according to claim 22, wherein The buffer comprises a mixture of acetic acid and sodium acetate or citric acid and sodium citrate, with a pH in the range of about 4.0 to about 7.

9.

24. The pharmaceutical composition according to any one of claims 1 to 23, which is a hydrocolloid. The pharmaceutical composition according to claim 24 , which is a transparent to translucent colloid.

26. The pharmaceutical composition according to any one of claims 1 to 25, which is suitable for sustained release of cinacalcet.

27. A unit dosage form comprising the pharmaceutical composition according to any one of claims 1 to 26.

28. The unit dosage form according to claim 27, which is suitable for intravenous administration.

29. The unit dosage form according to claim 27, which is suitable for intraperitoneal administration.

30. A method for controlling parathyroid hormone (PTH) levels, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-26 or the unit dosage form according to any one of claims 27-29.

31. A method for regulating calcium and phosphorus in the blood, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-26 or the unit dosage form according to any one of claims 27-29.

32. A method for treating primary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 26 or the unit dosage form according to any one of claims 27 to 29.

33. A method for treating secondary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 26 or the unit dosage form according to any one of claims 27 to 29.

34. A method for treating hypercalcemia, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-26 or the unit dosage form according to any one of claims 27-29.

35. The method according to any one of claims 30 to 34, wherein The administration is intravenous administration.

36. The method according to any one of claims 30 to 34, wherein The administration is intraperitoneal administration.

37. The method according to any one of claims 30 to 34, wherein The administration occurs before, during, or immediately after the subject's dialysis procedure.

38. The method of claim 37, wherein: The administration is performed during the subject's dialysis procedure.

39. The method according to any one of claims 30 to 38, wherein Administration of the pharmaceutical composition provides sustained release of cinacalcet.

40. The method according to any one of claims 30 to 38, wherein Administration of the pharmaceutical composition will not induce phlebitis.

41. A method for preparing a composition of polymeric micellar cinacalcet, comprising: dissolving at least one amphiphilic block copolymer and cinacalcet or a pharmaceutically acceptable salt thereof in an organic solvent to form a first mixture; adding the first mixture to water or an aqueous solution while stirring; optionally, removing the organic solvent to produce transparent to translucent colloidal cinacalcet micelles; and optionally, adding one or more pharmaceutically acceptable excipients, carriers or diluents; or At least one amphiphilic block copolymer and cinacalcet or a pharmaceutically acceptable salt thereof are dissolved in an organic solvent to form a first mixture; the organic solvent is removed by evaporation to form a matrix; water or an aqueous solution is added to the matrix to produce transparent to translucent colloidal micelles; and optionally, one or more pharmaceutically acceptable excipients, carriers or diluents are added.

42. The method according to claim 41, wherein The organic solvent is selected from ethanol, acetone, acetonitrile, dichloromethane (DCM), isopropanol, ethyl acetate, tert-butanol and methanol.

43. The method according to claim 41, wherein The organic solvent is removed by evaporation or sublimation.

44. The method according to any one of claims 41 to 43, wherein The amphiphilic block copolymer is a diblock or triblock copolymer.

45. The method of claim 44, wherein: The diblock copolymer is a biodegradable polyester-block-methoxypolyethylene glycol (MePEG), and the triblock copolymer is a biodegradable polyester-block-polyethylene glycol (PEG)-block-polyester.

46. ​​The method of claim 45, wherein The polyester block is selected from the group consisting of poly(D,L-lactide), poly(L-lactide), poly(D-lactide), polyglycolide, poly(ε-caprolactone), and copolymers and mixtures thereof.

47. The method of claim 46, wherein The polyester block is poly(D,L-lactide) (PDLLA).

48. The method according to any one of claims 41 to 47, wherein The one or more pharmaceutically acceptable excipients, carriers or diluents are selected from the group consisting of buffers, osmotic pressure regulators, cryoprotectants, lyoprotectants, fillers, surfactants and solvents.

49. The method of claim 47, wherein The molecular weight of PDLLA ranges from about 750 to about 50,000.

50. The method according to any one of claims 45 to 49, wherein The molecular weight of MePEG or PEG ranges from about 750 to about 20,000.

51. The method of any one of claims 45-50, further comprising storing the frozen polymeric micellar cinacalcet at about -20°C for long-term storage.

52. The method of any one of claims 45-50, further comprising storing the lyophilized polymeric micellar cinacalcet at about 2°C to about 8°C for long-term storage.

53. The method of any one of claims 45-52, further comprising reconstituting the lyophilized polymeric micellar cinacalcet prior to administration.

54. The pharmaceutical composition according to any one of claims 1-26, for use in controlling parathyroid hormone (PTH) levels.

55. The pharmaceutical composition according to any one of claims 1-26, for use in regulating calcium and phosphorus in the blood.

56. The pharmaceutical composition according to any one of claims 1-26, for use in the treatment of primary hyperparathyroidism.

57. The pharmaceutical composition according to any one of claims 1 to 26, for use in the treatment of secondary hyperparathyroidism.

58. The pharmaceutical composition according to any one of claims 1-26, for use in the treatment of parathyroid cancer.

59. Use of cinacalcet or a pharmaceutically acceptable salt thereof and at least one amphiphilic block copolymer in the preparation of a medicament.

60. The use according to claim 59, wherein The drug is used to control parathyroid hormone (PTH) levels.

61. The use according to claim 59, wherein The drug is used to regulate calcium and phosphorus in the blood.

62. The use according to claim 59, wherein The medicine is used to treat primary hyperparathyroidism.

63. The use according to claim 59, wherein The medicine is used to treat secondary hyperparathyroidism.

64. The use according to claim 59, wherein The medicine is used to treat parathyroid cancer.

Images