CHEWABLE DOSAGE FORMS CONTAINING SITAGLIPTIN AND METFORMIN

The present invention provides a chewable dosage form having a matrix comprising: a combination of active pharmaceutical ingredients which is metformin hydrochloride and sitagliptin or a pharmaceutically acceptable salt thereof, fully or partially pregelatinized starch, a texture-modifying gum, a lubricant, an emulsifier, a flavoring agent, and a sweetener. The present invention also provides a method of treating diabetes, e.g., non-insulin dependent (Type 2) diabetes mellitus, comprising administering a therapeutically effective amount of the chewable dosage form to a mammalian patient in need thereof.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations useful for administering a combination of sitagliptin and metformin to a mammalian patient.

BACKGROUND OF THE INVENTION

Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.

Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine effects of insulin resistance and impaired insulin secretion. The treatment of type 2 diabetes typically begins with diet and exercise, followed by or antidiabetic monotherapy. For many patients, these regimens do not sufficiently control glycemia during long-term treatment, leading to a requirement for combination therapy within several years following diagnosis. However, co-prescription of two or more oral antidiabetic drugs may result in treatment regimens that are complex and difficult for many patients to follow. Combining two or more oral antidiabetic agents into a single tablet provides a potential regimen of delivering combination therapy without adding to the complexity of patients' daily regimens. The selection of effective and well-tolerated treatment is a key step in the design of a combination tablet. Moreover, it is essential that the components have complementary mechanisms of action and compatible pharmacokinetic profiles.

Metformin represents the only oral antidiabetic agent proven to reduce the total burden of microvascular and macrovascular diabetic complications and to prolong the lives of Type 2 diabetic patients. Furthermore, metformin treatment is often associated with reductions in body weight in overweight patients and with improvements in lipid profiles in dyslipidemic patients. Metformin hydrochloride is marketed in the U.S. and elsewhere as either immediate-release or extended-release formulations with tablet dosage strengths of 500, 750, 850, and 1000 milligrams.

Dipeptidyl peptidase-IV (DPP-4) inhibitors represent a class of agents developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. For example, oral administration of the specific DPP-4 inhibitors sitagliptin, vildagliptin, alogliptin, and saxagliptin to human Type 2 diabetics has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbA1clevels. For reviews on the application of DPP-4 inhibitors for the treatment of Type 2 diabetes, reference is made to the following publications: (1) A. H. Stonehouse, et al., “Management of Type 2 diabetes: the role of incretin mimetics,Exp. Opin. Pharmacother., 7: 2095-2105 (2006); (2) B. D. Green, et al., “Inhibition of dipeptidyl peptidase-IV activity as a therapy of Type 2 diabetes,”Exp. Opin. Emerging Drugs, 11: 525-539 (2006); (3) M. M. J. Combettes, “GLP-1 and Type 2 diabetes: physiology and new clinical advances,”Curr. Opin. Pharmacol., 6: 598-605 (2006); and R. K. Campbell, “Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus,”Ann. Pharmacother.,41: 51-60 (2007).

Sitagliptin phosphate having structural formula I below is the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3 -a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine.

Sitagliptin phosphate can be in the form of a crystalline monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Pat. No. 6,699,871, the contents of which are hereby incorporated by reference in their entirety. Crystalline sitagliptin phosphate monohydrate is disclosed in U.S. Pat. No. 7,326,708, the contents of which are hereby incorporated by reference in their entirety. Sitagliptin phosphate has been approved for marketing in several countries, including the U.S., Europe, Canada, and Mexico, for the treatment of Type 2 diabetes and is branded as JANUVIA™ in the U.S. and elsewhere. For reviews, see D. Drucker, et al., “Sitagliptin,”Nature Reviews Drug Discovery,6: 109-110 (2007); C. F. Deacon, “Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for Type 2 diabetes,”Exp. Opin. Invest. Drugs,16: 533-545 (2007); K. A. Lyseng-Williamson, “Sitagliptin,” Drugs, 67: 587-597 (2007); and B. Gallwitz, “Sitagliptin: Profile of a Novel DPP-4 Inhibitor for the Treatment of Type 2 Diabetes (Update),”Drugs of Today,43: 801-814 (2007).

Sitagliptin can also be provided as a sitagliptin tannate complex. International Pub. No. WO2015/160678 published Oct. 22, 2015 discloses a sitagliptin tannate complex or pharmaceutical compositions or pharmaceutically acceptable intermediates comprising such a complex. The publication indicates that the complex possesses a release property or profile in which the complex exhibits a negligible release rate at neutral pH, and an immediate release in acidic pH. According to the publication, this release property allows formulation of sitagliptin in oral dosage form that is easier to swallow and does not need a film layer because the sitagliptin tannate complex has a neutral taste in the mouth.

The combination of sitagliptin and metformin provides substantial and additive glycemic improvement in patients with Type 2 diabetes (B. J. Goldstein, et al., “Effect of Initial Combination Therapy with Sitagliptin, a DPP-4 Inhibitor, and Metformin on Glycemic Control in Patients with Type 2 Diabetes,”Diabetes Care,30: 1979-1987 (2007) and B. Gallwitz, “Sitagliptin with Metformin: Profile of a combination for the treatment of Type 2 diabetes,”Drugs of Today,43: 681-689 (2007). A fixed-dose combination of immediate-release of both metformin and sitagliptin has been approved for marketing in several countries, including U.S. and Mexico, for adult patients with Type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. The combination is branded as JANUMET™ in the U.S. JANUMET™ tablets contain 50 mg sitagliptin and either 500, 850, or 1000 mg metformin. Pharmaceutical compositions comprising fixed-dose combinations of immediate-release sitagliptin and immediate-release metformin are disclosed in U.S. Pat. No. 8,414,921.

U.S. Pat. Appl. Pub. No. 2010/0323011 also discloses pharmaceutical compositions comprising fixed-dose combinations of metformin, or a pharmaceutically acceptable salt thereof, coated with a form of the DPP-4 inhibitor sitagliptin or a pharmaceutically acceptable salt thereof. The publication discloses that the pharmaceutical compositions comprise an extended-release form of metformin, or a pharmaceutically acceptable salt thereof, and an immediate-release form of sitagliptin, or a pharmaceutically acceptable salt thereof.

While oral dosage forms that combine fixed doses of both sitagliptin and metformin represent an improved therapy over separate administration of the two active ingredients, further improvements to the dosage forms can result in further benefits to the patient population. For instance, oral dosage forms that are chewable may improve the combination therapy's appeal for patients, such as the elderly, who have difficulty swallowing a more rigid tablet or a capsule formulation of the combined active ingredients.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a chewable dosage form having a matrix comprising: a combination of active pharmaceutical ingredients which is metformin hydrochloride and sitagliptin or a pharmaceutically acceptable salt thereof

fully or partially pregelatinized starch,

a lubricant;

an emulsifier;

a flavoring agent; and

a sweetener.

In another aspect, the present invention provides a method of treating diabetes, e.g., non-insulin dependent (Type 2) diabetes mellitus, comprising administering a therapeutically effective amount of the chewable dosage form to a mammalian patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is directed to pharmaceutical compositions which are chewable dosage form.

In embodiment no. 1, the present invention provides a chewable dosage form having a matrix comprising:

a combination of active pharmaceutical ingredients which is metformin hydrochloride and sitagliptin or a pharmaceutically acceptable salt thereof;

fully or partially pregelatinized starch,

a lubricant;

an emulsifier;

a flavoring agent; and

a sweetener.

In embodiment no. 2, the present invention provides the chewable dosage form as set forth in embodiment no. 1, wherein the sum of the fully or partially pregelatinized starch and texture-modifying gum, is at least 10 wt. % of the matrix. In embodiment no. 3, the sum of the fully or partially pregelatinized starch and texture-modifying gum is 10-50 wt. % of the matrix. In embodiment no. 4, the sum of the fully or partially pregelatinized starch and texture-modifying gum is 10-30 wt. % of the matrix

In embodiment no. 5, the present invention provides the chewable dosage form as set forth in any one of embodiment nos. 1-4, wherein the emulsifier is glycerol monostearate or cetyl alcohol.

In embodiment no. 6, the present invention provides the chewable dosage form of any one of embodiment nos. 1-5, wherein the matrix further comprises an acidifier wherein the acidifier is citric acid, malic acid, acetic acid, lactic acid or tartaric acid. Preferably the acidifier is citric acid or malic acid. In certain embodiments, the acidifier is citric acid.

In embodiment no. 7, the present invention provides the chewable dosage form of any one of embodiment nos. 1-6, wherein the matrix further comprises a humectant, wherein the humectant is glycerin, propylene glycol, or cetyl alcohol.

In embodiment no. 8, the present invention provides the chewable dosage form of any one of embodiment nos. 1-7, wherein the fully or partially pregelatinized starch is partially pregelatinized starch. In embodiment no. 9, the pregelatinized starch is starch 1500.

In embodiment no. 10, the present invention provides the chewable dosage form of any one of embodiment nos. 1-9, wherein the texture-modifying gum is pectin, xanthan gum, carboxymethyl cellulose, gelatin, guar gum, gum Arabic, locus bean gum or a combination thereof.

In embodiment no. 11, the present invention provides the chewable dosage form of any one of embodiment nos. 1-10, wherein the lubricant is a vegetable oil lubricant, which is partially hydrogenated palm kernel, oil soy bean oil or coconut oil.

In embodiment no. 12, the present invention provides the chewable dosage form of any one of embodiment nos. 1-11, wherein the sweetener is a hydrogenated starch hydrolysate, a sugar alcohol, sucralose, glycyrrhizin or a pharmaceutically acceptable salt thereof, or a combination thereof.

In embodiment no. 13, the present invention provides the chewable dosage form of any one of embodiment nos. 1-12, wherein the flavoring agent is peppermint.

In embodiment 14, the present invention provides the chewable dosage form as set forth in embodiment no. 1, wherein the matrix comprises:

from 15 to 40 wt. % of the combination of active pharmaceutical ingredients;

from 10 to 25 wt. % of the fully or partially pregelatinized starch;

from 0.5 to 10 wt. % of the texture-modifying gum; and

from 5 to 20 wt. % of the lubricant.

In embodiment 15, the present invention provides the chewable dosage form as set forth in embodiment no. 14, wherein the matrix comprises:

from 0.5 to 10 wt. % of a combination of pectin and xanthan gum; and

from 5 to 20 wt. % of partially hydrogenated palm kernel oil.

The unit dosage strengths of sitagliptin free base anhydrate (active pharmaceutical ingredient) for inclusion into the soft chewable dosage forms as set forth in any one of embodiment nos. 1-15 are 25, 50 and 100 milligrams. Equivalent amounts of sitagliptin phosphate monohydrate to the stagliptin free base anhydrate are used in the pharmaceutical compositions, namely 32.125, 64.25, and 128.5 milligrams, respectively.

The unit dosage strengths of metformin hydrochloride (active pharmaceutical ingredient) for inclusion into the soft chewable dosage forms as set forth in any one of embodiment nos. 1-14 are 250, 500, 750, 850 and 1000 milligrams. These unit dosage strengths of metformin hydrochloride represent the dosage strengths approved in the United States for marketing to treat Type 2 diabetes.

Specific embodiments of dosage strengths for sitagliptin and metformin hydrochloride in any one of the chewable dosage forms as set forth in embodiment no. 1-4 are the following:

A preferred pharmaceutically acceptable salt of sitagliptin for any of the above-described embodiments is the dihydrogenphosphate salt of structural formula I above (sitagliptin phosphate). A preferred form of the dihydrogenphosphate salt is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are hereby incorporated by reference in their entirety.

Another preferred form of sitagliptin for any of the above-described embodiments is a sitagliptin tannate complex. A preferred form of this sitagliptin complex is the one prepared and disclosed in Example 1 of US Patent Application Publication No. 20170042922. Briefly, the sitagliptin tannate complex can be prepared by combining a salt or a free base form of sitagliptin in a suitable solvent with a dispersion of tannic acid in a suitable solvent, removing the liquid; washing the residue with a polar pharmaceutically acceptable liquid; drying the residue; and pulverizing the sitagliptin tannate complex into a free-flowing powder.

The preparation of sitagliptin and pharmaceutically acceptable salts thereof, are disclosed in U.S. Pat. No. 6,699,871.

Another aspect of the present invention is directed to a method of treating diabetes, e.g., non-insulin dependent (Type 2) diabetes mellitus, comprising administering a therapeutically effective amount of the chewable dosage form as described in any of the embodiments described above to a mammalian patient in need thereof. In preferred embodiments, the mammalian patient being treated is a human patient.

The terms “therapeutically effective amount” and similar descriptions such as “an amount efficacious for treatment” are intended to mean that amount of a pharmaceutical drug or combination of drugs that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a pharmaceutical drug that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. The dosage regimen utilizing a dosage form of the instant invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of Type II diabetes, and a prophylactically effective amount, e.g., for prevention of Type II diabetes.

The soft chewable dosage form contains food grade and compendial excipients only, and preferably are not of animal origin. The excipients for the soft chewable dosage forms can include, but are not limited to the following excipients: favorants, sweeteners, emulsifiers, binders, gums, fillers, texture, modifiers, absorbents, lubricants, mouth-feel enhancers, acidifiers, humectants, anti-sticking agents, anti-caking agents, wetting agents, colorants, and other excipients familiar to those skilled in the art. Optionally, in addition to sweeteners incorporated into the matrix to make the dosage forms palatable and appealing, other taste masking approaches may be used, such as encapsulation or complexation of the active ingredients.

The chewable dosage forms of the invention include a fully or partially pregelatinized starch which serve as a filler and impart the chewy texture of the soft chew dosage forms of the present invention. “Pregelatinized starch” as meant herein, and as disclosed in USP26/N21 refers to starch that has been chemically and/or mechanically processed to rupture all or part of the granules in the presence of water and is subsequently dried. “Fully or partially pregelatinized starch” as used herein, refers to a starch wherein at least some fraction of the starch is gelatinized, up to, and including, the entire quantity of the starch. As will be recognized by those formulators of skill in the art, fully pregelatinized starch is readily soluble in water.

Fully or partially pregelatinized starches also can function as binders and texture enhancers. Other bulking agents or fillers can also be included in the dosage forms of the invention along with the fully or partially pregelatinized starch. Such other bulking agents or fillers include polysaccharides, pharmaceutical gums, and polymers. Pharmaceutical gums such as xanthan gum, pectins, carboxymethyl cellulose, gelatin, and others known to those skilled in the art can impart the chewy texture of the soft chew dosage forms of the present invention.

Waxes may optionally be included the formulation so that the soft chew dosage forms do not stick together upon molding. Waxes, such as polyethylene glycol, are added into the formulations, preferably as a melt. The waxes also aid in maintaining the shape or form of the dosage form. Preferred waxes include polyethylene glycol 8000, polyethylene glycol 6000, or polyethylene glycol 3350. If present, the concentration in the dosage forms is from 0.1-10 wt. %, and preferably from 1-5 wt. %.

In certain embodiments, lubricants, anti-sticking agents, and anti-caking agents are included in the soft chewable dosage forms of the invention into the formulation to facilitate the manufacturing process. Inclusion of a vegetable oil such as partially hydrogenated palm kernel oil, soy bean oil, or coconut oil suitably serves this purpose.

Since the formulation contains both oils and excipients that are water-soluble, to facilitate the formation of a homogeneous mixture, incorporation of one or more emulsifiers is advantageous. A preferred emulsifier is glycerol monostearate, though others can be included, such as cetyl alcohol, which can also serve as a wetting agent. Other wetting agents such as sodium lauryl sulfate and polyethylene glycols can be included along with the emulsifier.

The chewable dosage forms of the present invention include flavoring agents. Suitable flavoring agents include peppermint, cherry, banana, mango, orange, pineapple, raspberry, strawberry, or vanilla.

The soft chewable dosage forms of the invention typically include hydrogenated starch hydrolysates, such as Lycasin® 85/55, as a bulk sweetener. Sugar alcohols can also serve as a sucrose substitute, and optionally, can be used with high intensity artificial sweeteners, such as sucralose and glycyrrhizin.

In some embodiments, the soft chewable dosage forms of the invention include humectants to maintain the forms' soft texture. A preferred humectant is glycerin, but other humectants such as propylene glycol and cetyl alcohol can serve as humectants.

In certain embodiments, the soft chewable forms of the invention include an acidifier such as citric acid, malic acid, acetic acid, lactic acid or tartaric acid.

In certain embodiments, a super-disintegrant, preferably sodium starch glycolate or similar disintegrant such as starch USP, starch 800, alginic acid, sodium croscarmellose, crospovidone, or polyplasdone can be added to aid in the disintegration of the soft chew dosage forms if swallowed wholly or in large pieces.

Some embodiments of the soft chew dosage forms of the invention include a preservative or a combination of preservatives into the formulation to prevent microbial contamination over the shelf life of the dosage form. Examples of such preservatives include, but are not limited to, sodium sorbate, methyl paraben, and others well-known to those skilled in the art.

The individual amount of each excipient in the soft chew dosage forms of the invention can vary considerably depending on factors, such as the drug load, desired texture, image size and other factors known to those skilled in the art.

EXAMPLES

The following examples are provided to more clearly describe the present invention and should not be construed to limit the scope of the invention.

Preparation and of a Sitagliptin/Metformin HCl Soft Chew Dosage Form

Equipment and Supplies

Preparation

All weights were determined on an analytical balance.

1. 2600 mg (±78 mg) of sitagliptin phosphate monohydrate was weighed into a glass mortar.

2. Ingredients 2a-2d (shown below) were added in the order presented below to the mortar in Step 1, mixing for at least 60 seconds after each addition (geometric dissolution) using a stainless steel spatula until the powder blend appeared to be uniformly mixed.a. 2600 mg (±78 mg) Starch 1500b. 5200 mg (±156 mg) Starch 1500c. 8600 mg (±258 mg) Starch 1500d. 2000 mg (±600 mg) metformin hydrochloride

3. 12000 mg (±360 mg) of partially hydrogenated palm kernel oil and 500 mg (±15 mg) of glyceryl monostearate were weighed into a 25 mL beaker.

5. 33400 mg (±1002 mg) of maltitol syrup and 10000 mg (±300 mg) of glycerin were weighed into a 400 mL beaker.

6. 3000 mg (±90 mg) of pectin and 500 mg (±15 mg) of xanthan gum were added to the contents of the beaker in step 5. The contents were mixed using a stainless steel spatula for about 60 seconds. The resulting melt and the PEG 8000 from step 5 were added to the contents in the vessel of step 4.

7. The mixture formed in Step 6 was heated on a hotplate to 80-90° C.

8. The mixture formed in Step 3 was added to the mixture of Step 7 and the resulting mixture was mixed with a stainless steel spatula for about 60 seconds.

9. The mixture formed in Step 4 was added to the mixture of Step 8 and the resulting mixture was mixed with a stainless steel spatula for about 60 seconds.

10. The powder blend formed in Step 1 was added to the mixture of step 9, and the resulting mixture was mixed with a stainless spatula for about 3 minutes until a dough-like matrix formed.

11. 2500 mg (±75 mg) of the matrix of Step 10 was weighed out and formed into a sphere. This step was repeated to form a plurality of soft chew dosage forms

12. The soft chew dosage forms from step 11 were allowed to set for 2 hours.

13. The soft chew dosage forms were individually wrapped with wax paper. The wrapped, dosage forms were stored in a 250 mL amber glass bottle fitted with a screw cap at 20±5° C.

Pharmacokinetic Analysis of Patients Following Administration of Soft Chew Dosage Forms

A study was conducted to estimate the pharmacokinetic (PK) parameters (AUCO-∞, AUC0-last, Cmax, Tmaxand apparent terminal t1/2) following a single dose administration of the sitagliptin/metformin 50 mg/ 500 mg soft chew dosage forms of Example 1. The study was an open-label, 3-period, fixed sequence study. Sixteen healthy, non-tobacco using male and female subjects were enrolled to complete the study with at least 12 subjects. In each period, subjects received a single soft chew dosage form of Example 1 administered as one of three treatments under fed conditions. Treatment A consisted of administration of the reference Janumet™ 50 mg/ 500 mg oral tablet. Treatment B consisted of administration of the 50 mg/500 mg soft chew dosage forms of Example 1.

As shown inFIG. 1, for the observed sitagliptin plasma concentration, the Cmax, AUCO0-lastand AUC0-∞ arithmetic values were less than 8% higher following the administration of the dosage forms of Example 1 when compared with the arithmetic values resulting from the administration of the 50 mg/ 500 mg Janumet™ mg oral tablet.

As shown inFIG. 2, for the observed metformin plasma concentration, the Cmax, AUCO0-lastand AUC0-∞ arithmetic values were approximately 12-18% higher following the administration of the dosage forms of Example 1 when compared with the GM values resulting from the administration of the 50 mg/ 500 mg Janumet™ oral tablet.