WO2013110085A1

WO2013110085A1 - Oral dosage forms for delivering metformin and sitagliptin

Info

Publication number: WO2013110085A1
Application number: PCT/US2013/022589
Authority: WO
Inventors: Zhiqun Shen; Min Michael He; Fang-Yu Liu
Original assignee: Handa Pharmaceuticals, Llc
Priority date: 2012-01-20
Filing date: 2013-01-22
Publication date: 2013-07-25

Abstract

The present invention provides oral dosage forms and compositions for delivering metformin and sitagliptin to a subject as well as related methods of treatment, use, and manufacture. In one embodiment, a multi-layer oral dosage form containing metformin and sitagliptin is provided. The oral dosage form includes a first layer with a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof and a hydrophobic rate controlling excipient. The oral dosage form also includes a second layer with a therapeutically effect amount of sitagliptin or a pharmaceutically acceptable salt thereof.

Description

ORAL DOSAGE FORMS FOR DELIVERING METFORMIN AND

SITAGLIPTIN

PRIORITY DATA

This application claims the benefit of United States Provisional Patent

Application Serial No. 61/589,198, filed on January 20, 2012, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to oral dosage forms for the delivery of metaformin and sitagliptin, as well as related methods. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences. BACKGROUND OF THE INVENTION

Metformin is a FDA approved pharmaceutically active antihyperglycemic agent. Metformin improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents in that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. In contrast to sulfonylureas, metformin does not produce hypoglycemia in either patients with Type 2 diabetes or normal subjects (except in special

circumstances) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with Type 2 diabetes by slowing the inactivation of incretin hormones. When administered together, metformin and sitagliptin can act as an effective therapy for subjects with Type 2 diabetes. Unfortunately, existing metformin and sitagliptin containing oral dosage forms are required to be

administered twice daily. Oral dosage forms containing metformin and sitagliptin formulated for once-a-day administration would allow for less frequent dosing and potentially better patient compliance. SUMMARY OF THE INVENTION

Accordingly, the present invention provides oral dosage forms and

compositions for delivering metformin and sitagliptin to a subject as well as related methods of treatment, use, and manufacture. In one embodiment, a multi-layer oral dosage form containing metformin and sitagliptin is provided. The oral dosage form includes a first layer with a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof and a hydrophobic rate controlling excipient. The oral dosage form also includes a second layer with a therapeutically effect amount of sitagliptin or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of manufacturing a release multi-layer metformin and sitagliptin containing multi-layer oral dosage form is provided. The method includes admixing a hydrophobic rate controlling excipient and metformin to form a metformin-containing admixture. A separate sitagliptin-containing admixture is provided by admixing at least one pharmaceutical excipient and sitagliptin and the metformin and sitagliptin containing admixtures are formed into a solid multi-layer oral dosage form. The oral dosage form is cured for a period of 1 to 3 hours at a temperature of 65°C to 75°C to form a multi-layer oral dosage form.

In yet a further embodiment, a method of treating a medical condition in a subject for which the combination of metformin and sitagliptin is an effective treatment is provided. The method includes administering to the subject, an oral dosage form as described herein to provide a therapeutically effective dose of both metformin and sitagliptin. One example of a condition that can be treated using the disclosed oral dosage forms and related methods is Type II diabetes. BREIF DESCIRPTION OF DRAWINGS

FIG. 1 is a cross-sectional view of one embodiment of a tri-layer oral dosage form of the present invention.

FIG. 2 is a cross-sectional view of an additional embodiment of a tri-layer oral dosage form of the present in vention.

DETAILED DESCRIPTION

Before the present oral dosage forms and methods regarding metformin and sitagliptin are disclosed and described, it is to be understood that this in vention is not limited to the particular process steps and materials disclosed herein, but is extended to equivalents thereof, as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

It should be noted that, the singular forms "a," "an," and, "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a lubricant" includes reference to one or more of such excipients, and reference to "the carrier" includes reference to one or more of such carriers.

As used herein, the terms an "oral dosage form" refers to a pharmaceutical formulation or composition that has been shaped or sized suitable for oral

administration. Generally speaking, such an "oral dosage form" may include a mixture of one or more active agents with a carrier or other excipients.

As used herein, "carrier" or "pharmaceutically acceptable carrier" refers to a substance with which a drug may be combined to achieve a specific dosage form, formulation, or composition for delivery to a subject. In the some aspects of the present invention, the carriers used may or may not enhance or otherwise impact drug delivery. As a general principle, carriers should not react with the drug in a manner that substantially degrades or otherwise adversely affects the drug, except that carriers may react with a drug to prevent it from exerting a therapeutic effect until the drug is released from the carrier. Further, the carrier, or at least a portion thereof must be suitable for administration into a subject along with the drug. The carrier can include a variety of components and excipients.

As used herein "metformin" refers to the well-known pharmaceutically active ingredient having the IUPAC name N,N-dimethylimidodicarbonimidic diamide as well as its pharmaceutically acceptable salts such as metformin hydrochloride.

As used herein "sitagliptin" refers to the well-known pharmaceutically active ingredient having the IUPAC name (R)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyraz^

amine as well as its pharmaceutically acceptable salts such as sitagliptin phosphate.

As used herein "placebo" as it refers to a layer of the oral dosage form refers to a layer or region of the oral dosage form that is free or substantially free of any pharmaceutically active agent. The placebo layer present in embodiments of the present invention has no active agent or substantially no active agent upon

manufacture of the oral dosage form but under some circumstances, small amounts of active agent may migrate from the metformin or sitagliptin layers into the placebo layer following manufacture. Such a layer is still considered to be a placebo layer.

As used herein, "subject" refers to a mammal that may benefit from the administration of a drug composition or method of this invention. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. In one specific aspect, a subject is a human.

As used herein, an "effective amount" or a "therapeutically effective amount" of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is thought to be effective. Moreover, an "effective amount" of a non-active agent or drug, such as a carrier, excipients, alkaline substance or other component refers to an amount that is suitable to perform a desired role or task, or achieve a desired result. Such amount is generally the minimum amount required, but can be any suitable amount that is considered non-toxic or that would otherwise interfere with the desired function or activity of the formulation or composition in which the ingredient is included. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount" or a "therapeutically effective amount" may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The

determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine.

As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result. For example, a composition that is

"substantially free of particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles. In other words, a composition that is "substantially free of an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.

As used herein, the term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint.

As used herein the terms "formulation" and "composition" may be used interchangeably and refer generally to the combination of at least two ingredients or agents, such as an active agent or drug and a carrier. As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience.

However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. In addition, various embodiments and example of the present invention are referred to herein along with alternatives for the various components thereof. It is understood that such embodiments, examples, and alternatives are not to be construed as defacto equivalents of one another, but are to be considered as separate and autonomous representations of the present invention.

Concentrations, amounts, levels and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the in vention to those preferred embodiments. To the contrary, it is intended to cover alternatives, variants, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

As outlined above, the present invention provides for a multi-layer oral dosage form containing metformin and sitagliptin. The oral dosage form includes a first layer with a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof and a hydrophobic rate controlling excipient. The oral dosage form also includes a second layer with a therapeutically effect amount of sitagliptin or a pharmaceutically acceptable salt thereof. In one embodiment, the oral dosage form is formulated for once-a-day administration.

The oral dosage forms of the present invention can take a variety of forms known in the art including, but not limited to a tablet or a caplets. In one particular embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a bi-layer tablet. In yet a further embodiment, the oral dosage form is a tri- layer tablet. When the oral dosage form includes a third layer the third layer can be a placebo layer. In some embodiments the placebo layer can include or be a hydrophobic rate controlling excipient. In another embodiment, the placebo layer can be substantially free of hydrophobic rate controlling excipients and, when configured as in FIG. 2, the layer can function to prevent the migration of the hydrophobic rate controlling excipient from migrating into the immediate release sitagliptin layer. When present in the placebo layer, the hydrophobic rate controlling excipient can be the same rate controlling excipient as used in the metformin layer or it can be a distinct rate controlling excipient. Other pharmaceutically acceptable excipients may also be incorporated into the placebo layer. When the oral dosage form is a tri-layer oral dosage form with a placebo layer, the oral dosage form can be configured as shown in FIG. 1. Specifically, the metformin-containing first layer 2 is disposed centrally with the sitagliptin-containing second layer 4 disposed adjacent to the metformin-containing first layer and the placebo layer 6 disposed opposite the sitagliptin-containing second layer and adjacent to the metformin-containing first layer. In another embodiment, the tri-layer oral dosage form with a placebo layer can be configured as shown in FIG. 2, namely that the placebo layer 12 is disposed centrally with the sitagliptin-containing second layer 14 being disposed adjacent to the placebo layer and the metformin-containing first layer 16 being disposed opposite the sitagliptin-containing second layer and adjacent to the placebo layer.

The oral dosage forms of the present invention include metformin, or a pharmaceutically acceptable salt of metformin, in therapeutically effecti ve amounts. Amounts of metformin in the oral dosage form can range from amounts equivalent to about 250 mg to about 1200 mg of metformin hydrochloride. In one embodiment, the metformin can be present in an amount equivalent to 500 mg to about 1000 mg of metformin hydrochloride. The amount of metformin in an oral dosage form can vary depending upon a variety factors including, but not limited to the indication for being treated by the oral dosage form and the subject being treated. Typically, the metformin can comprise about 10 wt% to about 85 wt% of the oral dosage form. In one embodiment, the metformin can comprise about 20 wt% to about 80 wt% of the oral dosage form. In another embodiment, the metformin can comprise about 50 wt% to about 80 wt% of the oral dosage form. As defined above, metformin includes its pharmaceutically acceptable salts. Accordingly, in one embodiment, the metformin is metformin hydrochloride. The metformin-containing layer of the oral dosage form of the present invention can provide for extended release of the metformin.

The oral dosage forms also include sitagliptin or its pharmaceutically acceptable salts. The sitagliptin can be present in the oral dosage form in an amount equivalent to about 25 mg to about 150 mg of sitagliptin free base. In one embodiment, the sitagliptin can be present in the oral dosage form in an amount equivalent to about 25 mg to about 100 mg of sitagliptin free base. As defined above sitagliptin includes both sitagliptin itself as well as its pharmaceutically acceptable salts. Accordingly, in one embodiment, the sitagliptin is sitagliptin phosphate. In another embodiment, the sitagliptin phosphate is anhydrous sitagliptin phosphate. In still a further embodiment, the sitagliptin phosphate can comprise about 1 wt% to about 10 wt% of the oral dosage form. In still a further embodiment, the sitagliptin phosphate can comprise about 1 wt% to about 8 wt% of the oral dosage form. In one embodiment, the sitagliptin-containing layer can provide for immediate release of the sitagliptin.

The oral dosage forms and compositions of the present invention can be formulated to provide extended release of the metformin from the metformin- containing layer of the multi-layer oral dosage form. In some aspects, the extended release profile of the oral dosage forms can be achieved, at least in part, through the inclusion of a hydrophobic rate controlled excipient in the oral dosage form. Non- limiting examples of hydrophobic rate controlling excipients that can be used include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, a free wax acid, an ester of a free wax acid, triglycerides, saturated fatty acids (e.g., stearic acid), propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax, and mixtures thereof. In one embodiment, the hydrophobic rate controlling excipient can be a hydrogenated vegetable oil. Non-limiting examples of hydrogenated vegetable oil that can be used include hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated arachis oil, hydrogenated soybean oil, and combinations thereof.

The hydrophobic rate controlling excipient can be present in the oral dosage form or composition in nearly any amount that is sufficient to provide a composition or oral dosage form with desired physical or drug release performance characteristics. In one aspect, the amount of hydrophobic rate controlling excipients can be present in only the metformin-containing layer. In another embodiment, a hydrophobic rate controlling excipient can be present in both the metformin-containing layer and a placebo layer.

In one embodiment, the amount of hydrophobic rate controlling agent present in the oral dosage form can be from about 50 mg to about 400mg. In another embodiment, the hydrophobic rate controlling excipient can be present in the oral dosage form in amounts of about 75 mg to about 275 mg. In a further embodiment the amount of rate controlling excipient can vary depending on the amount of the metformin present in the oral dosage form and/or the presence or absence of a placebo layer. Generally, the hydrophobic rate controlling excipient can comprise about 10 wt% to about 25 wt% of the oral dosage form. In one embodiment, the hydrophobic rate controlling excipient can comprise about 15wt% to about 20 wt% of the oral dosage form. In another embodiment, the hydrophobic rate controlling excipient comprises about 15 wt% to about 25 wt% of the metformin-containing layer of the oral dosage form. The oral dosage forms and compositions of the present invention can also include one or more additional pharmaceutically acceptable excipient. Non-limiting examples of excipients that can be included in the oral dosage forms and

compositions include fillers, binders, lubricants, glidants, antiadherents, flavoring agents, disintegrants, surfactants, anti-oxidants, and coloring agents. The excipients can be present in a single layer or multiple layers of the oral dosage form and need not be homogenous across the dosage form.

Non-limiting examples of acceptable fillers, sometimes referred to as diluents, include mannitol, lactitol, dextrose, sucrose, maltose, starch, microcrystalline cellulose, lactose, isomalt, and combinations thereof.

Examples of binders that can be used in the oral dosage forms and

compositions include, but are not limited to copovidone, hydroxypropylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, sugars, starches, and combinations thereof.

Glidants or lubricants that can be used in the oral dosage forms and

compositions of the present invention include, but are not limited to colloidal silicon dioxides, talc, magnesium stearate, dibasic calcium phosphate, sodium stearyl fumarate, calcium stearate, stearic acid, polyethylene glycols, silicon dioxide, and combinations thereof.

Examples of surfactants that can be included in the oral dosage forms and compositions include without limitation, sodium lauryl sulfate, polysorbates, sodium taurochloate, and combinations thereof.

Flavoring agents that can be used in the present invention include without limitation peppermint, spearmint, wintergreen, cinnamon, coconut, coffee, chocolate, vanilla, menthol, liquor ice, anise, apricot, caramel, pineapple, strawberry, raspberry, grape, cherry, mixed berry, tropical fruits, mint, and mixtures thereof.

Anti-oxidants can be used to enhance the stability of the active agents in the oral dosage form. The antioxidant can be any known antioxidant effect at providing the requisite stability enhancement of one or both of the active agents. In one embodiment the antioxidant can be butylated hydroxytoluene.

The oral dosage forms of the present invention can, in some embodiments, be coated with a coating. Various coating types known in the art can be utilized in the present invention. Examples of coating types include without limitation, film coatings, enteric or pH dependent coatings, delayed release coatings, and the like. In one embodiment, the oral dosage form can be coated with a film coating. When an enteric or pH dependent coating is included with the oral dosage form or composition, any known and compatible enteric coating material can be used. Non-limiting examples of such material can include zein, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, or mixtures thereof.

The metformin and sitagliptin containing oral dosage forms of the present invention can be made utilizing known pharmaceutical manufacturing techniques including wet and dry granulation, melt blending, extrusion, and the like. When done using wet granulation, the wet granulation can be accomplished in a high-shear granulator and dried in a fluid-bed dryer. In some embodiments the sitagliptin layer can be made using dry granulation to avoid the formation of the monohydrate form of sitagliptin phosphate. Whether granulated by wet or dry granulation, the granulates can be sized using a Comil or Fitzmill. All admixing and blending steps of in the manufacture can be accomplished using known blending devices or methods including bin blending or a V-blender. Compression of the oral dosage forms into tablets or caplets can be accomplished using any method known in the industry such as a rotary tablet press.

In one embodiment, a metformin and sitagliptin containing multi-layer oral dosage form is provided. The method includes admixing a hydrophobic rate controlling excipient and metformin to form a metformin-containing admixture. A separate sitagliptin-containing admixture is provided by admixing at least one pharmaceutical excipient and sitagliptin and the metformin and sitagliptin containing admixtures are formed into a solid multi-layer oral dosage form. The oral dosage form is cured for a period of 1 to 3 hours at a temperature of 65°C to 75°C to form a multi-layer oral dosage form. In one embodiment, the method can further include the step of tableting the solid composition to form multi-layer tablets prior to the curing step.

In yet a further embodiment, a method of treating a medical condition in subject for which the combination of metformin and sitagliptin is an effective treatment is provided. The method includes administered to the subject an oral dosage form as described herein to provide a therapeutically effective dose of both metformin and sitagliptin. One example of a condition that can be treated using the disclosed oral dosage forms and related methods is Type II diabetes.

In an additional embodiment, the present invention includes use of metformin and sitagliptin in the preparation of a medicament useful for treatment of a subject with a condition responsive to metformin and sitagliptin administration. In some aspects, such a medicament may include a composition or oral dosage form as disclosed herein. EXAMPLES

EXAM PLE 1 - Manufacturing process for multi-layermetformin and sitagliptin- containing oral dosage compositions

Compositions and oral dosage forms in accordance with embodiments of the present invention can be made according to the following methodology. An amount of metformin hydrochloride can be sieved and disposed into a suitable container with an amount of a hydrophobic rate controlling excipient (e.g. Lubritab). A pre-weighed amount of ethyl cellulose (Surelease® Clear) is slowly charged into the container while mixing manually until agglomerates are formed. The wet agglomerates are passed through a sieve and then dry granulated in an oven under 60°C to final moisture level of NMT 0.5% (loss-on-drying). The dry metformin-containing granulates are then sieved. The dry metformin-containing granulates are blended with colloidal silicone dioxide and talc in a plastic bag to form a metformin-containing final blend.

The sitagliptin layer is prepared by admixing premeasured amounts of anhydrous sitagliptin phosphate, butylated hydroxytoluene (BTH), and hydroxypropyl cellulose (L-HPC LH21) in a suitable container. Lactitol monohydrate is dissolved in water to form a solution and the lactitol solution is added into the suitable container containing the powdered mixture of sitagliptin, BTH, and L-HPC. The ingredients are mixed to form granulates. The wet granulation is sieved and then dried in an oven under 60°C to final moisture level of NMT 1.5% (loss-on-drying). The dried granulation is sieved and blended with colloidal silicone dioxide and sodium stearyl fumarate (PRUV⁸) in a plastic bag to form a sitagliptm-containing final blend. Following formation of the metfomiin-containing and sitagliptin-containing final blends the final blends are compressed to form a multi-layer oral dosage form. Specifically, the metformin-containing final blend is compressed to form a first layer using a rotary press with about 2-6 KN to form the metformin layer. The sitagliptin layer can then be compressed onto the metformin layer utilizing a rotary press with about 7-14 KN force. The final oral dosage form can be cured by heating at a temperature of 65°C to 80°C for about 2 hours.

The oral dosage form can optionally be coated using a known coating compounds such as Opadry YS- 1-4060 white. The coating can be done by aqueous dissol ution of the coating using in a pan coater or the coating can be an organic solvent based coating system. The coating can provide a target weight gain of approximately 1.5%.

In one embodiment, the oral dosage form can be a tri-layer oral dosage form and can include, in addition to the metformin and sitagliptin layers, a placebo layer. In embodiments where the oral dosage form includes a placebo layer, the metformin and sitagliptin layers can be produced as described above. The placebo layer can be made by mixing a hydrophobic rate controlling excipient (e.g. hydrogenated vegetable oil - Lubritab®), dibasic calcium phosphate, lactitol monohydrate and colloidal silicon dioxide in a suitable container. The tri-layer tablet can be compressed in an additive manner as described above, with a first layer being compressed with compression forces of 2-6 KN, a second layer being compressed into the first layer to form a bi- layer form with compression forces of 7-14 KN, and compressing a the third and final layer to the bi-layer form utilizing a compressive force of 23-33 KN. The

configuration of the layers can vary depending on the desired configuration of the oral dosage form. EXAMPLES 2-4 - Multi-layer Metformin/Sitagliptin-containing tablets

Metformin and sitagliptin-containing oral dosage forms, namely tablets, in accordance with one embodiment of the present invention are prepared in a similar manner as described in Example 1 and have the compositional formulation set forth in Table I.

TABLE I

egeta e , ype

EXAMPLE 5 - Dissolution testing of Examples 2-4

The dissolution of tablets of Examples 2-4 is performed in a dissolution medium of 900 mL deionized water. The dissolution was accomplished utilizing a basket-type dilution apparatus (USP Type 1) with a stir rate of paddle 75 rpm without sinker. Results for the dissolution are shown in Table II,

TABLE 11

EXAMPLES 6-8 - Multi-layer Metformin/Sitagliptin-containing tablets

Multi-layer metformin and sitaglipim-contaimng oral dosage forms, namely tablets, in accordance with one embodiment of the present invention are prepared in a similar manner as described in Example 1 and have the compositional formulation set forth in Table III

TABLE III

The oral dosage tablets of Example 6-8 were coated with an immediate release of Opadry YS- 1-4060 White, As exemplary of the weight gain of the tablets, the weight gain of the oral dosage tablets of Example 6 are shown below in Table IV,

TABLE IV

EXAMPLE 9 - Dissolution testing of Examples 6-8

The dissolution of tablets of Examples 6-8 is performed in a dissolution medium of 900 rriL deioriized water. The dissolution was accomplished utilizing a basket-type dilution apparatus ( USP Type 1) with a stir rate of paddle 75 rpm without sinker. Results for the dissolution are shown in Table V. Dissolution in the same medium and under the same conditions for the related commercially available products of Glumetza and Januvia are also shown below in Table V.

TABLE V

EXAMPLE 10 - Stability testing for Example 6

After curing, the stability of the tablets of Example 6 was tested. Six of the cured tablets of Example 6 were paclvaged into a 50 cc HDPE bottle, with one-g silica gel desiccant pouch in the bottle. The tablets in the bottle were placed in a stability chamber at 60°C/60%RH and stability testing was performed at various time intervals. Results of the stability testing are shown in the Tables VI and VII below. Impurity profiles for sitagliptin are shown in Table VI and impurity profiles for metformin are shown in Table VII.

TABLE VI

TABLE VII

EXAMPLE 11 - Stability testing for Example 7

After curing, the stability of the tablets of Example 7 was tested in a manner similar to the testing set forth in Example 10. Six of the cured tablets of Example 6 were packaged into a 50 cc HDPE bottle, with one-g silica gel desiccant pouch in the bottle. The tablets in the bottle were placed in a stability chamber at 60°C/60%RH and stability testing was performed at various time intervals. Results of the stability testing are shown in the Tables VIII and IX below. Impurity profiles for sitagliptin are shown in Table VIII and impurity profiles for metformin are shown in Table IX.

TABLE VIII

TABLE IX

It has to be understood that the above-described various types of compositions, dosage forms and/or modes of applications are only illustrative of preferred embodiments of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention and the appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that variations including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.

Claims

CLAIMS What is claimed is:

1. A multi-layer oral dosage form for containing metformin and sitagliptin, comprising:

a first layer including therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof and a hydrophobic rate controlling excipient, and

a second layer comprising a therapeutically effect amount of sitagliptin or a pharmaceutically acceptable salt thereof.

2. The oral dosage form of claim 1, wherein the dosage form is a bi-layer tablet.

3. The oral dosage form of claim 1 , further comprising a third layer, said third layer being a placebo layer containing no active agent.

4. The oral dosage form of claim 3, wherein the third layer includes a

hydrophobic rate controlling excipient.

5. The oral dosage form of claim 3, wherein the oral dosage form is configured such that the metformin-containing first layer is disposed centrally with the sitagliptin-containing second layer being disposed adjacent to the metformin- containing first layer and the placebo layer being disposed opposite the sitagliptin-containing second layer and adjacent to the metformin-containing first layer.

6. The oral dosage form of claim 3, wherein the oral dosage form is configured such that the placebo layer is disposed centrally with the sitagliptin-containing second layer being disposed adjacent to the placebo layer and the metfoimin- containing first layer being disposed opposite the sitagliptin-containing second layer and adjacent to the placebo layer.

7. The oral dosage form of claim 1 , wherein the metformin is present in the oral dosage form in an amount equivalent to about 250 mg to about 1200 mg of metformin hydrochloride.

8. The oral dosage form of claim 1 , wherein the metformin is present in the oral dosage form in an amount equivalent to about 500 mg to about 1000 mg of metformin hydrochloride.

9. The oral dosage form of claim 1 , wherein the metformin comprises about 10 wt% to about 85 wt% of the oral dosage form.

10. The oral dosage form of claim 1, wherein the metformin is present as

metformin hydrochloride.

11. The oral dosage form of claim 1, wherein the metformin comprises about 50 wt% to about 80 wt% of the oral dosage form.

12. The oral dosage form of claim 1, wherein the sitagliptin is present in the oral dosage form in an amount equivalent to about 25 mg to about 150 mg of sitagliptin free base.

13. The oral dosage form of claim 1, wherein the sitagliptin is present in the oral dosage form in an amount equivalent to about 25 mg to about 100 mg of sitagliptin free base.

14. The oral dosage of claim 1, wherein the sitagliptin is present as sitagliptin phosphate.

15. The oral dosage of claim 13, wherein the sitagliptin phosphate is anhydrous sitagliptin phosphate.

16. The oral dosage form of claim 13, wherein the sitagliptin phosphate comprises about 1 wt% to about 10 wt% of the oral dosage form.

17. The oral dosage form of claim 13, wherein the sitagliptin phosphate comprises about 1 wt% to about 8 wt% of the oral dosage form.

18. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, a free wax acid, an ester of a free wax acid, propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax, triglycerides, saturated fatty acids, and mixtures thereof.

19. The oral dosage form of claim 1, wherein hydrophobic rate controlling

excipient is a hydrogenated vegetable oil.

20. The oral dosage form of claim 19, wherein the hydrogenated vegetable oil is selected from the group consisting of hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated arachis oil, hydrogenated soybean oil, and combinations thereof.

21. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient comprises about 15 wt% to about 25 wt% of the metformin- containing first layer.

22. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient is present in the oral dosage form in an amount of about 50 mg to about 400 mg.

23. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient comprises about 10 wt% to about 25 wt% of the oral dosage form.

24. The oral dosage form of claim 1, wherein the metformin-containing layer is an extended release layer.

25. The oral dosage form of claim 1, wherein the sitagliptin layer is an immediate release layer.

26. The oral dosage form of claim 1, wherein the sitagliptin-containing second layer includes an antioxidant.

27. The oral dosage form of claim 26, wherein the antioxidant is butylated

hydroxytoluene.

28. The oral dosage form of claim 1, wherein the oral dosage form includes at least one component selected from the group consisting of a filler, a binder, a lubricant, a glidant, an antiadherent, a flavoring agent, a disintegrant, a surfactant, and a coloring agent.

29. The oral dosage form of claim 28, wherein the oral dosage form includes a filler selected from the group consisting of mannitol, lactitol, dextrose, sucrose, maltose, starch, microcrystalline cellulose, lactose, isomalt, and combinations thereof.

30. The oral dosage form of claim 28, wherein the oral dosage form includes a surfactant selected from a group consisting of sodium lauryl sulfate, polysorbates, sodium taurochloate, and combinations thereof.

31. The oral dosage form of claim 28, wherein the oral dosage form includes a binder selected from the group consisting of copovidone,

hydroxypropylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, sugars, starches, and combinations thereof.

32. The oral dosage form of claim 28, wherein the oral dosage form includes a glidant or lubricant selected from the group consisting of colloidal silicon dioxides, talc, magnesium stearate, dibasic calcium phosphate, sodium stearyl fumarate, calcium stearate, stearic acid, polyethylene glycols, silicon dioxide, and combinations thereof.

33. The oral dosage form of claim 1, wherein the oral dosage is coated with a film coating.

34. The oral dosage form of claim 1, wherein the oral dosage form is a member selected from the group consisting of: a tablet, a capsule, granules, beads, and combinations thereof.

35. The oral dosage form of claim 1, wherein the oral dosage form is a tablet.

36. The oral dosage form of claim 1, wherein the oral dosage form is formulated for once-a-day administration.

37. A method of treating or preventing a medical condition in a subject, for which the combination of metformin and sitagliptin is an effective treatment, comprising:

administering a therapeutically effective amount of metformin and sitagliptin in an oral dosage form as recited in any of the preceding claims to the subject.

38. The method of claim 37, wherein the medical condition is type II diabetes.

39. A method of manufacturing a mult-layer metformin and sitagliptin containing multi-layer oral dosage form, comprising admixing a hydrophobic rate controlling excipient and metformin to form a metformin-containing admixture; admixing at least one pharmaceutical excipient and sitagliptin to form a sitagliptin-containing admixture; forming the admixture into a solid multilayer composition; and curing the solid composition for a period of 1 to 3 hours at a temperature of

65°C to 75°C to form a controlled release oral dosage composition.

40. The method of claim 39, further comprising the step of tableting the solid composition to form a multi-layer tablets prior to the curing step.

41. The method of claim of claim 39, wherein the oral dosage form is selected from he group consisting of a tablet and a caplet.

42. Use of metformin and sitagliptin in the preparation of a medicament useful for treatment of a condition in a subject that is responsive to metformin and sitagliptin administration, said medicament being suitable for oral

administration to said subject and including components in accordance with claim 1.