Treatment of weight regain after discontinued use of anorectic drugs

Abstract

A method of slowing the weight regain after cessation of an anorectic drug (GLP-1 analog) where a coion targeted gut hormone secretagogue is administered.

Description

TREATMENT OF WEIGHT REGAIN AFTER DISCONTINUED USE OF ANORECTICDRUGSCOPYRIGHT NOTICEA portion of the disclosure of this patent contains material that is subject to copyright protection. The copyright owner has no objection to the reproduction by anyone of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all copyright rights whatsoever.BACKGROUND OF THE INVENTIONField of the Invention

[0001] The present invention relates to a treatment to prevent, stop or retard weight regain after discontinuation of anorectic drugs such as GLP-1 analogs.Description of Related Art

[0002] Weight gain (regain) is common after discontinuation of anorectic drugs such as GLP1 analogs, Wegovy (Ozempic), Zepbound (Mounjaro) or older drugs like Saxenda (Victoza). Weight gain after discontinuation is associated with weight controlling hormones called metabolic adaptation.BRIEF SUMMARY OF THE INVENTION

[0003] The present invention relates to the discovery that certain colon targeted gut hormone secretagogues such as butyrate compositions, if delivered to the colonbypassing the stomach and upper digestive system, can be used to slow or stop weight gain after cessation of an anorectic drug.

[0004] Accordingly, in one embodiment, there is a method of slowing weight gain after cessation of an anorectic drug comprising: a) selecting a composition for oral administration comprising a colon targeted gut hormone secretagogue, the composition formulated to release the colon targeted gut hormone secretagogue in a colon targeted delivery system, bypassing the stomach and upper intestine and releasing in the colon; and b) administering an effective amount of a colon targeted gut hormone secretagogue.DETAILED DESCRIPTION OF THE INVENTION

[0005] While this invention is susceptible to embodiment in many different forms, there is shown in the drawings, and will herein be described in detail, specific embodiments with the understanding that the present disclosure of such embodiments is to be considered as an example of the principles and not intended to limit the invention to the specific embodiments shown and described. In the description below, like reference numerals are used to describe the same, similar, or corresponding parts in the several views of the drawings. This detailed description defines the meaning of the terms used herein and specifically describes embodiments in order for those skilled in the art to practice the invention.DEFINITIONS

[0006] The terms “about” and “essentially” mean ±10 percent.

[0007] The terms "a" or "an", as used herein, are defined as one or as more than one. The term "plurality", as used herein, is defined as two or as more than two. The term "another", as used herein, is defined as at least a second or more. The terms "including" and / or "having", as used herein, are defined as comprising (i.e., open language). The term "coupled", as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically.

[0008] The term “comprising” is not intended to limit inventions to only claiming the present invention with such comprising language. Any invention using the term comprising could be separated into one or more claims using “consisting” or “consisting of” claim language and is so intended.

[0009] Reference throughout this document to "one embodiment", "certain embodiments", “an embodiment", or similar terms 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, the appearances of such phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments without limitation.

[0010] The term "or", as used herein, is to be interpreted as an inclusive or meaning any one or any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; Aand B; A and C; B and C; A, B, and C". An exception to this definition wili occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.

[0011] It is further noted that the claims may be drafted to exclude any element which may be optional. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.

[0012] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. To the extent such publication may set out definitions of a term that conflict with the explicit or implicit definition of the present disclosure, the definition of the present disclosure controls.

[0013] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0014] The drawings featured in the figures, if any are for the purpose of illustrating certain convenient embodiments of the present invention and are not to be consideredas limitation thereto. The term “means" preceding a present participle of an operation indicates a desired function for which there is one or more embodiments, i.e., one or more methods, devices, or apparatuses for achieving the desired function and that one skilled in the art could select from these or their equivalent in view of the disclosure herein, and use of the term “means" is not intended to be limiting.

[0015] As used herein, the term "treating" refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject.

[0016] As used herein, the term “condition or disorder” refers to any time a person has quit or ceased using an anorectic drug. Included are the disease states noted herein. In one embodiment, the mammal is a human.

[0017] As used herein, a “compound" of the present invention includes all compounds described herein.

[0018] The compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as x-ray diffraction patterns, solubility, and melting point.

[0019] Certain of the compounds, described herein, contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of thepresent invention includes mixtures of stereoisomers, as weli as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. Also, included within the scope of the present invention are the individual isomers of the compounds, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers, thereof, in which one or more chiral centers are inverted.

[0020] Typically, but not absolutely, the compounds herein include the salts of the present compositions and include the pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, thethiodide, thmethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention, and these should be considered to form a further aspect of the invention.

[0021] The “administering” of a composition of the present invention can refer to orai administration. As described elsewhere herein, the compounds are so formulated to be taken so as to bypass the upper digestive tract and stomach or taken rectally to deliver the composition to the colon, i.e., large intestine.

[0022] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. It has been discovered that a gut hormone secretagogue such as butyrate slows the weight regain after cessation of an anorectic drug such as GLP1 analogs, but only when it is delivered directly to the colon, while administration orally to the stomach or upper intestine is ineffective.

[0023] The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes, within its scope, amounts effective to enhance normal physiological function. A therapeutically effective amount will produce a “therapeutic effect”.

[0024] For use in therapy, therapeutically effective amounts of a compound of the present invention, as well as salts thereof, are presented as a pharmaceutical composition formulated to release in a colon targeted delivery system which bypasses the stomach and upper intestine.

[0025] The present invention provides pharmaceutical compositions that include effective amounts of a compound, as herein described, or a salt thereof, and one ormore pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition, as well as consistent with the mode of administration, i.e., oral or rectal.

[0026] In accordance with another aspect of the present invention, there is also a process provided for the preparation of a pharmaceutical formulation, including admixing a compound of the present invention or salts thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients for delivery directly to the colon.

[0027] A therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the type of colon targeted delivery system selected are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant, physician, or veterinarian. Regardless, an effective amount of a compound of the present invention for the treatment of humans ceasing anorectic drugs generally, should be in the range of 0.01 mg / kg to 100 mg / kg body weight of recipient (mammal) per day. More often, the effective amount should be in the range of 0.3 mg / kg to 70 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be from 21 mg to 4900 mg. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day, such that the total daily dose is the same. An effective amount of a salt or solvatethereof, may be determined as a proportion of the effective amount of the compound of the present invention per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.

[0028] Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of an active ingredient per unit dose. Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the present invention, depending on the condition being treated, the route of administration, and the age, weight, and condition of the recipient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmaceutical art.

[0029] The compounds of the present invention, or a salt thereof, are administered by a targeted drug delivery system. In one embodiment, the delivery systems may be employed for targeting drug delivery to the colon and bypassing the upper digestive system and stomach. Such drug delivery systems include, but are not limited to, covalent linkage compositions, polymer coated compositions, compositions embedded in matrices, time-released compositions, redox-sensitive polymer compositions, bioadhesive compositions, micropartical coating compositions, and osmotic delivery compositions. Suitable compositions include those containing polysaccharides, such as chitosan, pectin, chondroitin sulphate, cyclodexthn, dextrans, guar gum, inulin, amylose, and locust bean gum. The compounds may also be coupled with soluble polymers. Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, orpolyethyleneoxidepolylysine substituted with palmitoyi residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. Those of particular effectiveness in the present invention include embodiments comprising sustained-release core of tablet or capsule coated with single or double layer of colon sensitive material, Phloral® (from Intract Pharma, Ltd.) or Phloral® with additional layer separating Phloral® from content of the tablet systems. Phloral® is a dual action (pH and enzymatic activity of the microbiota) product for delivery to the colon. Those skilled in the art will appreciate the use of such compositions for the purposes of targeting delivery of the compounds of the present invention, or a salt thereof, to the colon of the recipient being treated. The methods for the formulation of such compositions for targeted delivery are within the skill in the art, in view of this disclosure.

[0030] The compounds of the present invention or a salt thereof may be employed alone or in combination with other therapeutic agents. The compound(s) of the present invention and the other pharmaceutically active agent(s) are administered together or at the same time. The amounts of the compound(s) of the present invention and the other pharmaceutically active agent(s) involve the relative timings of administration which will be selected in order to achieve the desired combined therapeutic effect. The administration in combination with a compound of the present invention or a salt or solvate thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition, including both compounds;or (2) separate pharmaceutical compositions, each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, wherein one treatment agent is administered first and the other second, or vice versa. Such sequential administration should be close in time or remote in time.

[0031] The present invention provides pharmaceutical compositions that include effective amounts of a compound as herein described, or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition and consistent with the mode of administration, i.e., oral or rectal.

[0032] In accordance with another aspect of the present invention, there is also provided a process for the preparation of a pharmaceutical formulation, including admixing a compound of the present invention or salts thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] The present invention provides pharmaceutical compositions that include effective amounts of a compound as herein described, or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition and consistent with the mode of administration, i.e., oral or rectal.

[0034] In accordance with another aspect of the present invention, there is aiso provided a process for the preparation of a pharmaceutical formulation, including admixing a compound of the present invention or salts thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0035] The compounds are formulated in one embodiment in compositions comprising a gut hormone secretagogue core, a neutral polymer first layer and a colon releasing outer layer. The compositions so formulated will be designed to give an effective dosage to the colon. The first layer is applied in one embodiment at a thickness of about 5-100 microns. In one embodiment, the thickness of the first layer is 10-50 microns.

[0036] As used herein, the term “GLP1 analogs” refers to anorectic drugs such as semaglutide, tirzepatide, liraglutide.

[0037] As used herein, the term “gut hormone secretagogue” refers to compound(s) which are agonists or intestinal / colon receptors in L-cells. The receptors are TRG-5, GPR-40, GPR-41 , GPR-43, GPR-120 and recently identified L-glutamine receptor, likely TAS1R3: J Mol Endocrinol. 2020 Apr;64(3):133-143.EXAMPLES

[0038] Example 1 : 300 obese patients were selected based on inclusion criteria (BMI >35 kg / m2 with at least one comorbidity or BMI 27-34.9 kg / m2 with at least two comorbidities) and treated with 2.4 mg of Wegovy for 20 weeks, when patients lost 11% of weight on average. At this time patients remaining in the study were randomized based on % weight loss to three groups. Group 1 : continued treatment with Wegovy; Group 2: treatment with placebo; Group 3: treatment with BKR-017. Each group withtreated with assigned treatment for additional 12 months. Weight was measured every month initially and later every two months.

[0039] Example 2: 300 obese patients were selected based on inciusion criteria (BMI >35 kg / m2 with at least one comorbidity or BMI 27-34.9 kg / m2 with at least two comorbidities) and treated with 2.4 mg of Wegovy for 16 months, when weight loss plateaued. At this time patients remaining in the study were randomized based on % weight loss to three groups. Group 1 : continued treatment with Wegovy; Group 2: treatment with placebo; Group 3: treatment with BKR-017. Each group with treated with an assigned treatment for additional 15 months. Weight was measured every month initially and later every 3 / 4 months.

[0040] In both studies treatment with BKR-017 significantly slowed down rate of weight regain demonstrating benefits of replacement of Wegovy treatment (if need to be stopped for reasons of adverse effects, insurance coverage etc.) with BKR-017

[0041] Those skilled in the art to which the present invention pertains may make modifications resulting in other embodiments employing principles of the present invention without departing from its spirit or characteristics, particularly upon considering the foregoing teachings. Accordingly, the described embodiments are to be considered in all respects only as illustrative, and not restrictive, and the scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description or drawings. Consequently, while the present invention has been describedwith reference to particular embodiments, modifications of structure, sequence, materials, and the like apparent to those skilled in the art still fall within the scope of the invention as claimed by the applicant.

Claims

What is ciaimed is:

1. A method of slowing weight gain after cessation of an anorectic drug comprising: a) selecting a composition for oral administration comprising a colon targeted gut hormone secretagogue, the composition formulated to release the colon targeted gut hormone secretagogue in a colon targeted delivery system, bypassing the stomach and upper intestine and releasing in the colon; and b) administering an effective amount of a colon targeted gut hormone secretagogue after cessation of the anorectic drug.

2. The method according to claim 1 wherein the colon targeted gut hormone secretagogue is a nutrient.

3. The method according to claim 2, wherein the coion targeted gut hormone secretagogue nutrient is selected from the group consisting of butyrate and glutamine.

4. The method according to claim 1 wherein the anorectic drug is selected from the group consisting of semaglutide, tirzepatide, and liraglutide.

5. The method according to claim 1 wherein the gut hormone secretagogues are selected from the group consisting of synthetic analogs of butyrate activating GPR-41 and -43, L-glutamine synthetic analogs activating L-glutamine receptor, likely TAS1 R3, synthetic analogs of bile acids activating TRG-5 (bile acid receptor), and analogs of long chain fatty acids, activating GPR-40, GPR-120 receptors.

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