Antidiabetic pharmaceutical compositions and preparation method thereof

Abstract

An oral dosage form of an antidiabetic pharmaceutical composition comprises a core portion, an outer portion, and a controlled membrane film sandwiched therebetween. The core and outer portions respectively comprise a first antidiabetic agent and a second antidiabetic agent, such as metformin HCl and sitagliptin phosphate, each at a therapeutically effective amount. The controlled membrane film encapsulates the core portion and is provided with at least one passageway for allowing the first antidiabetic agent to release out when the oral dosage form is in an aqueous environment, such as in the gastrointestinal (GI) tract of a subject. The oral dosage form is configured, upon a single-dose oral administration, to provide a maximum plasma concentration of the first antidiabetic agent in the subject from approximately 7.5 to 15 hours after administration. A method for manufacturing the oral dosage form of the antidiabetic pharmaceutical composition is also provided.

Claims

1. An oral dosage form of a pharmaceutical composition for managing diabetes or prediabetes in a subject, comprising: a core portion comprising at least one first antidiabetic agent, each at a therapeutically effective amount wherein the at least first antidiabetic agent comprises metformin hydrochloride (metformin HCl); an outer portion comprising at least one second antidiabetic agent, each at a therapeutically effective amount; and a controlled membrane film encapsulating the core portion and sandwiched between the core portion and the outer portion, wherein the controlled membrane film is provided with at least one passageway configured to allow the at least one first antidiabetic agent to release out of the core portion therethrough when the oral dosage form is in an aqueous environment; wherein: the oral dosage form realizes a controlled release of the at least one first antidiabetic agent such that upon a single-dose oral administration, the oral dosage form provides a maximum plasma concentration of the at least one first antidiabetic agent in the subject from approximately 7.5 to 15 hours after administration; when the oral dosage form is test in a USP Type II apparatus at approximately 50 rpm at approximately 37° C. in 900 ml of a medium having a pH of approximately 6.8, the metformin hydrochloride exhibits a dissolution profile such that upon contacting the oral dosage form with the medium: Less than 30% of the metformin hydrochloride is released at approximately 2 hours; 20-60% of the metformin hydrochloride is released at approximately 4 hours; 50-92% of the metformin hydrochloride is released at approximately 8 hours; no less than 60% of the metformin hydrochloride is released at approximately 12 hours; and no less than 80% of the metformin hydrochloride is released at approximately 16 hours.

2. The oral dosage form of claim 1, wherein the metformin HCl has a dosage form of approximately 250-1000 mg.

3. The oral dosage form of claim 1, wherein the metformin hydrochloride exhibits a dissolution profile such that upon contacting the oral dosage form with the medium: 25-60% of the metformin hydrochloride is released at approximately 4 hours; and 55-85% of the metformin hydrochloride is released at approximately 8 hours.

4. The oral dosage form of claim 2, wherein the oral dosage form provides a mean maximum plasma concentration (C.sub.max) of metformin from approximately 0.5*X ng/ml to approximately 1.6*X ng/ml, based on administration of the oral dosage form comprising X mg of metformin HCl, wherein X is in a range of approximately 250-1000.

5. The oral dosage form of claim 2, wherein the oral dosage form provides a mean maximum AUC.sub.0-t from approximately 7*Y hr*ng/mL to approximately 16*Y hr*ng/mL, based on administration of the oral dosage form comprising Y mg of metformin HCl, wherein Y is in a range of approximately 250-1000.

6. The oral dosage form of claim 1, wherein the at least one second antidiabetic agent comprises at least one DDP-4 inhibitor, or a pharmaceutically acceptable salt thereof.

7. The oral dosage form of claim 3, wherein the at least one DIP-4 inhibitor comprises one or more of sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, dutogliptin, or berberine.

8. The oral dosage form of claim 7, wherein the at least one second antidiabetic agent comprises sitagliptin phosphate, having a dosage form of approximately 25-100 mg and having an immediate release formulation.

9. The oral dosage form of claim 8, wherein when the oral dosage form is tested in a USP Type I apparatus at approximately 75 rpm at approximately 37° C. in 900 ml of 0.025 mol/L sodium chloride solution, the sitagliptin phosphate exhibits a dissolution profile such that upon contacting the oral dosage form with the medium: more than 25% of the sitagliptin phosphate is released at 10 min.

10. The oral dosage form of claim 9, wherein the sitagliptin phosphate exhibits a dissolution profile such that upon contacting the oral dosage form with the medium: more than 80% of the sitagliptin phosphate is released at 60 min.

11. The oral dosage form of claim 1, wherein the at least one second antidiabetic agent comprises one or more of: a sulfonylurea or a pharmaceutically acceptable salt thereof; a meglitinide or a pharmaceutically acceptable salt thereof; a thiazolidinedione or a pharmaceutically acceptable salt thereof; a sodium-glucose transporter 2 (SGLT2) inhibitor or a pharmaceutically acceptable salt thereof; or an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof.

12. The oral dosage form of claim 11, wherein the at least one second antidiabetic agent has an immediate release formulation and comprises one of: dapagliflozin having a dosage strength of approximately 2.5-10 mg; glipizide having a dosage strength of approximately 1.25-10 mg; glyburide having a dosage strength of approximately 1.25-10 mg; repaglinide having a dosage strength of approximately 0.5-5 mg; nateoglinide having a dosage strength of approximately 30-60 mg; pioglitazone having a dosage strength of approximately 15-45 mg; rosiglitazone having a dosage strength of approximately 1-4 mg; acarbose having a dosage strength of approximately 12.5-100 mg; or miglitol having a dosage strength of approximately 12.5-100 mg.

13. The oral dosage form of claim 1, further comprising one or both of: an inner seal film sandwiched between the core portion and the controlled membrane film, configured to provide a protective coating for the core portion encapsulated therein; and an outer seal film coating an outer surface of the outer portion, configured to provide a protective coating for the outer portion encapsulated therein.

14. The oral dosage form of claim 13, wherein at least one of the inner seal film or the outer seal film comprises at least one film-forming polymer, each selected from the group consisting of hypromellose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose, polyvinylpyrrolidone (PVP), and polyvinyl alcohol and polyethylene glycol (PEG).

15. The oral dosage form of claim 14, wherein the inner seal film or the outer seal film has a ratio of approximately 0.4% to 40% by weight of the oral dosage form.

16. The oral dosage form of claim 15, wherein the ratio is approximately 2% to 10% by weight of the oral dosage form.

17. The oral dosage form of claim 14, wherein at least one of the inner seal film or the outer seal film further comprises at least one of a plasticizer, or a pigment, or a dispersing agent, or an antioxidant.

18. The oral dosage form of claim 1, wherein a number of the at least one passageway is two.

19. The oral dosage form of claim 18, wherein each of the at least one passageway is arranged on each side of the controlled membrane film.

20. The oral dosage form of claim 19, wherein each of the at least one passageway is arranged within ±5 mm of a center of each side of the controlled membrane film.

21. The oral dosage form of claim 20, wherein each of the at least one passageway is arranged within ±2 mm of the center of each side of the controlled membrane film.

22. The oral dosage form of claim 1, wherein each of the at least one passageway has a diameter of approximately 0.30-2.00 mm.

23. The oral dosage form of claim 22, wherein the diameter is in a range of 0.40-0.60 mm.

24. The oral dosage form of claim 1, wherein each of the at least one passageway has a depth of approximately 0.10-2.00 mm.

25. The oral dosage form of claim 24, wherein the depth is in a range of 0.30-1.40 mm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a schematic diagram of a dosage form of the pharmaceutical composition according to some embodiments of the disclosure;

(2) FIGS. 2A and 2B respectively show the dissolution profiles of metformin HCl and sitagliptin phosphate of a sample oral dosage form (i.e. Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure);

(3) FIGS. 3A and 3B respectively show the linear and semi-logarithmic plots of mean plasma concentrations of metformin HCl versus time for the reference formulation (“Reference”) and the test formulation (“Test”, i.e., Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure) in subjects under fasting condition; and

(4) FIGS. 4A and 4B respectively show the linear and semi-logarithmic plots of mean plasma concentrations of metformin HCl versus time for the reference formulation (“Reference”) and the test formulation (“Test”, i.e., Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure) in subjects under fed condition.

DETAILED DESCRIPTION

(5) In the following, with reference to the above-mentioned drawings of various embodiments disclosed herein, the technical solutions of the various embodiments of the disclosure will be described in a clear and fully understandable way. It is noted that the described embodiments represent merely a portion, but not all, of the embodiments of the disclosure. Based on the described embodiments of the disclosure, those ordinarily skilled in the art can obtain other embodiment(s), which shall come within the scope sought for protection by the disclosure.

(6) In a first aspect, the present disclosure provides a dosage form of a pharmaceutical composition that is specifically used for treating a subject with diabetes or prediabetes.

(7) Herein the dosage form is preferably an oral dosage form that is taken by the subject orally, and the subject can be, but is not limited to, a human, and can also be yet another insulin-producing mammal, such as a monkey, a chimpanzee, a dog, a cat, etc.

(8) In the dosage form disclosed herein, the pharmaceutical composition comprises two or more antidiabetic agents, each having a different action of mechanism and together having an additive, complementary, and/or synergistic effect in glycemic control. According to some embodiments, one of the two or more antidiabetic agents comprises a biguanide or a pharmaceutically acceptable salt thereof. Preferably, the biguanide can be metformin, or a pharmaceutically acceptable salt thereof (e.g. metformin hydrochloride). In addition to the biguanide, the two or more antidiabetic agents in the oral dosage form of the pharmaceutical composition further comprise one or more other types of antidiabetic medications, such as a sulfonylurea, a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, a sodium-glucose transporter 2 (SGLT2) inhibitor, or an alpha-glucosidase inhibitor, etc.

(9) In the dosage form of the pharmaceutical composition, each of the two or more antidiabetic agents can be further configured to have a dosage and/or a formulation that is optimized such that when the dosage form is orally administered in the subject, the two or more antidiabetic agents can complementarily and synergistically exert their respective antiglycemic effects to thereby realize a optimized therapeutic effect on the subject. In other words, the dosage(s) and/or formulation(s) of the two or more antidiabetic agents are respectively optimized in the dosage form so as to allow a maximally synergistic complementation of their respective action of mechanism once the dosage form of the pharmaceutical composition is taken up by the subject. According to some embodiments of the dosage form, the dosages and/or formulations for the two or more antidiabetic agents contained therein are designed or configured to be optimized based on their respective PK/PD profiles in the subject.

(10) In the dosage form of the pharmaceutical composition provided herein, any one of the two or more antidiabetic agents can be configured to be in an immediate-release formulation or alternatively in a controlled release formulation according to their respective PK/PD profiles that have been established.

(11) Regarding the immediate-release formulation of an antidiabetic agent in an oral dosage form of the pharmaceutical composition, the antidiabetic agent can be provided as granules, spheroids, beads, particles, pellets (hereinafter collectively referred to as “multiparticulates”), etc. An amount of the multiparticulates which is therapeutically effective to provide the desired dose of drug over time may be placed in a capsule or may be incorporated in any other suitable oral form.

(12) Regarding the controlled-release formulation of an antidiabetic agent in an oral dosage form of the pharmaceutical composition, it can be realized by arranging the antidiabetic agent at a core of the dosage form, and the core is further coated with a controlled membrane film which is configured to realize a controlled release of the core-residing antidiabetic agent.

(13) FIG. 1 illustrates a structural diagram of an oral dosage form of the pharmaceutical composition according to certain embodiments of the present disclosure. As illustrated in the figure, the oral dosage form 001 of the pharmaceutical composition substantially comprises a core portion 100 comprising at least one first antidiabetic agent and an outer portion 200 comprising at least one second antidiabetic agent.

(14) A controlled membrane film 150 is sandwiched between the core portion 100 and the out portion 200. One or more delivery passageways (e.g. orifices, pores, holes, or alike) 151 are arranged on the controlled membrane film 150, which are configured to provide delivery passageways for the at least one second antidiabetic agent in the core portion 100 to get out of the controlled membrane film 150, so as to realize a controlled release or an extended release thereof. In FIG. 1, only two delivery passageways 151 are shown, yet it is noted that it is for illustration purposes only, and there is no limitation on the number of delivery passageways arranged in the controlled membrane film 150. Optionally, each of the delivery passageways can be further provided with a soluble plug (not shown in the figure), such as a water soluble material (e.g. gelatin) or an enteric material, which is configured to seal the passageways but can dissolve or leach in a water solution (e.g. GI fluid) to thereby open the delivery passageways to allow the at least one first antidiabetic agent in the core portion 100 to release. Herein, the controlled membrane film 150 can comprise from about 1% to about 7%, preferably about 1.5% to about 4%, of the whole oral dosage form in mass weight. In certain preferred embodiments of the disclosure, the dosage form contains two passageways that are configured to provide the desired pharmacokinetic parameters of the formulation.

(15) Herein, the controlled membrane film 150 can be a semipermeable membrane by being permeable to the passage of external fluid such as water and biological fluids and being impermeable to the passage of the antidiabetic drug in the core. As such, the controlled membrane film 150 can comprise at least one insoluble polymer. Non-limiting examples for an insoluble polymer that can be used for forming the controlled membrane film 150 include a cellulose ester, a cellulose diester, a cellulose triester, a cellulose ether, a cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, or cellulose acetate butyrate, etc. Other suitable polymers are described in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210 which are incorporated herein by reference. For example, one membrane material as such can be cellulose acetate CA-398-10, which comprises an acetyl content of 39.3%-40.3% and is commercially available from Eastman Fine Chemicals.

(16) Herein optionally, the controlled membrane film 150 can comprise at least one insoluble polymer and at least one soluble excipient (i.e. pore-forming agent) which are mixed together with one another. The at least one soluble excipient may optionally include at least one pore-forming agent and or at least one plasticizer. The major compositions in the controlled membrane film 150 and their ratios are summarized in Table 1.

(17) TABLE-US-00001 TABLE 1 Main ingredients in the controlled membrane film of the oral dosage. INGREDINT Preferred More Preferred Polymer 50-99% 75-95%  Pore-forming agent  0-40% 2-20% Plasticizer 0-25% or 0-30% 0-15%

(18) Optionally, the controlled membrane film 150 can comprise one or more insoluble polymers as described above and at least one pore-forming agent. The at least one pore-forming agent increases the volume of fluid (water and biological fluid) penetrating into the core to enable the dosage form of the pharmaceutical composition to dispense substantially all of the antihyperglycemic drug through the passageway and/or the porous membrane. The pore-forming agent can be a water-soluble material or an enteric material. Some examples of the preferred materials that are useful as pore-forming agent include sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof. The preferred pore-forming agent is PEG 400, PEG 3350, PEG 6000, and PEG 8000. The pore-forming agent comprises approximately 0 to about 40% of the total weight of the coating, most preferably about 2% to about 20% of the total weight of the coating. The pore-forming agent dissolves or leaches from the membrane film to form paths in the membrane film for the fluid to enter the core and dissolve the active ingredient. The pore-forming agent may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drug that is soluble under intestinal conditions. If the pore-forming agent is a drug, the present dosage form has the added advantage of providing an immediate release of the drug which is selected as the pore-forming agent.

(19) Optionally yet preferably, the controlled membrane film 150 may also be formed with certain excipients such as a plasticizer. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutyl succinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like. Depending on the particular plasticizer, amounts of from 0 to about 25%, and preferably about 2% to about 15% of the plasticizer can be used based upon the total weight of the coating.

(20) As used herein, the term “passageway” can refer to an opening (e.g. an aperture, orifice, bore, hole, or alike) of the controlled membrane film 150 allowing the release of the at least one antidiabetic agent that is encapsulated in the core portion 100 therethrough, and can also refer to a weakened region or an erodible region (e.g. an erodible plug that erodes in an aqueous environment) in the controlled membrane film 150 which can be induced to form an opening therein to thereby allow release of the at least one antidiabetic agent therethrough. A detailed description of a “passageway” can be found in U.S. Pat. Nos. such as U.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,063,064, 4,077,407, 4,088,864, 4,783,337, and 5,071,607, the disclosures of which are hereby incorporate by reference. In certain embodiments, the passageways of the controlled membrane film 150 in the oral dosage form 001 are formed by mechanical or laser drilling. In other embodiments, the passageways are formed by making an indentation onto the core prior to the membrane coating to form a weakened area of the membrane at the point of the indentation.

(21) Optionally, the oral dosage form of the pharmaceutical composition can further comprise an inner seal film (not shown in FIG. 1), which is sandwiched between the core portion 100 and the controlled membrane film 150. The inner seal film substantially encapsulates the core portion 100, and is configured to provide a sealing means therefor before the core portion 100 is coated with the controlled membrane film 150 so that the characteristics of the active pharmaceutical ingredients included in the core portion of the oral dosage form of the pharmaceutical composition provided in the present disclosure is not influenced during the coating process.

(22) Herein, the inner seal film can comprise at least one film-forming polymer and one or more excipients that are pharmaceutically acceptable. Examples of a film-forming polymer include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol (PEG), hypromellose, or other suitable water-soluble polymer materials. The excipients contained in the outer seal film can similarly include plasticizer(s), pigment(s) (i.e. dye(s) or colorant(s)), dispersing agent(s), and antioxidant(s). The compositions of the plasticizers, pigments, dispersing agents and the antioxidants are known to people killed in the field. Examples of a plasticizer include polyethylene glycol grades 400 to 3350 and triethyl citrate. An example of a dispersing agent can be hydrated aluminum silicate (Kaolin). Examples of an antioxidant include α-tocopherol, γ-tocopherol, δ-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA), etc. The preferred antioxidant is propyl gallate. Herein the antioxidant serves to prevent oxidative degradation of the core portion of the oral dosage form of the pharmaceutical composition provided in the present disclosure.

(23) Herein, the relative amount of the inner seal film relative to the entire tablet, can vary within the scope of the invention and depend on the desirable drug load, which can range from about 0.5%-40%, and preferably from 2% to 10%, of the tablet dosage form by weight.

(24) According to certain embodiments, the at least one first antidiabetic agent in the core portion 100 of the oral dosage form 001 of the pharmaceutical composition comprises a biguanide or a pharmaceutically acceptable salt thereof. According to some embodiments of the oral dosage form, the biguanide can be metformin, and further optionally, the at least one first antidiabetic agent in the core portion 100 of the oral dosage form consists of metformin hydrochloride, which can have a dosage of 500-1000 mg. As such, with this substantial osmotic pump formulation provided by the oral dosage form provided herein, the biguanide or a pharmaceutically acceptable salt thereof can realize a controlled or sustained release after a subject takes the oral dosage form, yet without employing any expanding polymer.

(25) In certain embodiments, the core portion of the controlled release oral dosage form of metformin hydrochloride in the present invention further comprises, besides the at least one antidiabetic agent (i.e. antihyperglycemic drug or active drug, e.g. metformin hydrochloride), optionally at least one binding agent (also known as “binder”), and/or optionally at least one absorption enhancer, and/or optionally at least one lubricant, as listed in Table 2.

(26) TABLE-US-00002 TABLE 2 Main ingredients (active drug and excipients) in the core portion of the oral dosage. INGREDINT Preferred More Preferred Antidiabetic agent(s) 50-98%  75-95%  Binder(s) 0-40% 3-15% Absorption Enhancer(s) 0-20% 2-10% Lubricant(s) 0-10%  1-3%

(27) Herein, a binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone (also known as “providone” or “polyvidone”, shorted as “PVP”), hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents are water soluble such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent can constitute approximately about 0 to about 40%, preferably about 3% to about 15%, of the total weight of the core portion of the oral dosage form.

(28) The core portion may optionally comprise an absorption enhancer. The absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred absorption enhancers are fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-big (B-aminoethyl ether-N,N,N,N-tetraacetic acid (EGTA)). The core portion can comprise approximately 0 to about 20% of the absorption enhancer based on the total weight of the core portion, and most preferably about 2% to about 10% of the total weight of the core portion.

(29) A lubricant that can be used in the core portion of the oral dosage form provided herein can be any type of lubricants commonly known in the art such as magnesium stearate, stearic acid, sodium fumarate, glyceryl behenate, etc. and most preferably about 0.2% to about 2% of the total weight of the core portion.

(30) In addition to the abovementioned binder(s), absorption enhancer(s) and lubricant(s), other excipients that may optionally be included into the core portion of the oral dosage form can include pigments or dyes.

(31) In one specific embodiment of the oral dosage form, the core tablet (i.e. the core portion) can comprise metformin hydrochloride (i.e. active drug), Povidone (polyvinyl pyrrolidone, or PVP), USP (United State Pharmacopeia) grade (i.e. binder), sodium lauryl (i.e. absorption enhancer), and magnesium stearate (i.e. lubricant).

(32) According to certain embodiments, metformin hydrochloride can obtain peak plasma levels from 7.5 to 15 hours after administration under various conditions. Additionally, the controlled release of metformin can effectively reduce the gastrointestinal (GI) side effects (e.g. diarrhea, nausea, and vomiting, etc.) that are frequently caused by the agent. Based on FIGS. 3 and 4 for the plasma concentration figures of Controlled Release metformin/sitagliptin tablets at fasting and fed conditions, it achieves such effect to have the peak plasma levels between 7.5-15 hours.

(33) In embodiments where the at least one first antidiabetic agent in the core portion 100 is metformin or a pharmaceutically acceptable salt thereof, the controlled release oral dosage form provides a mean maximum plasma concentration (C.sub.max) of the drug that is about 700-1500 ng/ml, and preferably about 900-1250 ng/ml, based on administration of a controlled release oral dosage form providing 1000 mg/100 mg once-a-day dose of metformin/sitagliptin.

(34) In embodiments where the at least one first antidiabetic agent in the core portion 100 is metformin or a pharmaceutically acceptable salt thereof, the controlled release dosage form provides a mean AUC.sub.0-24hr that is about 7000-16000 ng.Math.hr/ml, and preferably about 9000-14000 ng.Math.hr/ml, based on administration of a controlled release oral dosage form providing 1000 mg/100 mg once-a-day dose of metformin/sitagliptin.

(35) Because of the above configuration, for the controlled-release dosage form of the pharmaceutical composition comprising a biguanide (e.g., metformin) that is suitable for once-a-day administration to human subjects with non-insulin-dependent diabetes mellitus (NIDDM) or prediabetes, the dosage form can control blood glucose levels for up to about 24 hours and can provide controlled release of the drug with a mean time to maximum plasma concentration (T.sub.max) of the drug from 7.5 to 15 hours after administration and a width at 50% of the height of a mean plasma concentration/time curve of the drug from about 6-15 hours.

(36) According to some embodiments, the at least one first antidiabetic agent in the core portion 100 may, in addition to the biguanide or a pharmaceutically acceptable salt thereof, further comprises one or more other types of antidiabetic agents, which can also realize a controlled release from the oral dosage form after the oral administration, because of the controlled membrane film 150 in the oral dosage form of the pharmaceutical composition.

(37) According to some other embodiments, the at least one first antidiabetic agent in the core portion 100 may comprise no biguanide but comprise one or more other types of antidiabetic agents, which can realize a controlled release from the oral dosage form after the oral administration.

(38) According to certain embodiments of the oral dosage form 001 of the pharmaceutical composition provided herein, the at least one second antidiabetic agent in the outer portion 200 can comprise at least one of a DPP-4 inhibitor (e.g. sitagliptin, saxagliptin, linagliptin, or alogliptin, etc.), a sulfonylurea (e.g. glipizide, or glyburide, etc.), a meglitinide (e.g. repaglinide, nateglinide, or mitiglinide, etc.), a thiazolidinedione (e.g. pioglitazone, or rosiglitazone, etc.), a SGLT2 inhibitor (e.g. canagliflozin, ertugliflozin, empagliflozin, or dapagliflozin, etc.), or an alpha-glucosidase inhibitor. In the oral dosage form of the pharmaceutical composition provided herein, because the at least one second antidiabetic agent residing in the outer portion 200 of the oral dosage form is substantially coated on the outer surface of the controlled membrane film 150, which is further released immediately after a the oral dosage form is taken, thus the at least one second antidiabetic agent has little influence on the controlled release of the at least one first antidiabetic agent (e.g. metformin HCl) from the core portion 100 of the oral dosage form.

(39) In the oral dosage form of the pharmaceutical composition provided herein, each of the at least one second antidiabetic agent can be configured to have a dosage and a formulation that correspondingly matches with a dosage and formulation of the at least one first antidiabetic agent (e.g. metformin) to thereby realize a complementary and synergistic effect. For example, the dosage and formulation of each of the at least one second antidiabetic agent can be configured based on the dosage and formulation of metformin and on the PK/PD profile of the each of the at least one second antidiabetic agent.

(40) In one specific embodiment, the oral dosage form of the pharmaceutical composition comprises an extended-release form of metformin having a dosage of approximately 500-1000 mg and an immediate-release form of the DPP-4 inhibitor sitagliptin having a dosage of approximately 25-100 mg, which reside in the core portion 100 and the outer portion 200 of the oral dosage form, respectively.

(41) In another specific embodiment, the oral dosage form of the pharmaceutical composition comprises a controlled-release form of metformin having a dosage of approximately 500-1000 mg and an immediate-release form of the SGLT-2 inhibitor dapagliflozin having a dosage of approximately 2.5-10 mg, which reside in the core portion 100 and the outer portion 200 of the oral dosage form, respectively.

(42) According to certain embodiments of the oral dosage form of the pharmaceutical composition provided herein, an outer seal film 250 is arranged to coat an outside surface of the outer portion 200 as also illustrated in FIG. 1. The outer seal film 250 is configured to provide a protective coating for the oral dosage form, so that the characteristics of the active pharmaceutical ingredients included in the oral dosage form are not influenced by the environment.

(43) Herein, the outer seal film 250 of the oral dosage form can have similar compositions as the inner seal film described above. Briefly, the outer seal film can comprise at least one pharmaceutically acceptable film-forming polymer and one or more pharmaceutically acceptable excipients.

(44) Examples of a film-forming polymer include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol (PEG), hypromellose, or other suitable water-soluble polymer materials. A particular form of HPMC for use as a film-forming polymer is HPMC 2910.

(45) The excipients contained in the outer seal film can similarly include plasticizer(s), pigment(s) (i.e. dye(s) or colorant(s)), dispersing agent(s), and antioxidant(s). Examples of a plasticizer include polyethylene glycol grades 400 to 3350 and triethyl citrate. An example of a dispersing agent can be hydrated aluminum silicate (Kaolin). Examples of an antioxidant include α-tocopherol, γ-tocopherol, δ-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA), etc. The preferred antioxidant is propyl gallate. Herein the antioxidant serves to prevent oxidative degradation of the core portion of the oral dosage form of the pharmaceutical composition provided in the present disclosure.

(46) Herein, the relative amount of the outer seal film relative to the entire tablet, can vary within the scope of the invention and depend on the desirable drug load, which can range from about 0.5%-40%, and preferably from 2% to 10%, of the tablet dosage form by weight.

(47) Herein, the relative amount of film-forming polymer(s) and plasticizer may vary within the scope of the invention. The plasticizer may be used independently or as a combination in various ratio. The relative amount of the plasticizer relative to the entire tablet, can vary within the scope of the invention and depend on the desirable drug load. In most cases, the plasticizer can constitute from about 0.1% to 10% by weight of the tablet dosage form, preferably from 1% to 8%. Additionally, the level of antioxidant can constitute from about 0.03% to 0.05%. If hydrated aluminum silicate is used as the dispersing agent, it can constitute from about 0.2% to 5% by weight of the tablet dosage form, preferably from 0.5% to 2%.

(48) The following examples further describe and demonstrate embodiments within the scope of the present invention. These embodiments are given solely for the purpose of illustration and are not intended to be construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope of the invention.

(49) According to some preferred embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of the sitagliptin or a pharmaceutically acceptable salt thereof. Herein, more specifically metformin or a pharmaceutically acceptable salt thereof corresponds to the at least one first antidiabetic agent arranged at the core portion 100 of the oral dosage form 001 as illustrated in FIG. 1, and sitagliptin or a pharmaceutically acceptable salt thereof corresponds to the second antidiabetic agent arranged at the outer portion 200 of the oral dosage form 001 as illustrated in FIG. 1. In these embodiments of the oral dosage form, these above two antidiabetic agents are substantially formulated into dosage forms suitable for the simultaneous administration.

(50) One particular solid dosage form as such relates to tablets comprising a fixed-dose combination of a controlled-release form of metformin hydrochloride coated with an immediate-release form of sitagliptin phosphate. Optionally, the unit dosage strength of the metformin hydrochloride for incorporation into the fixed-dose combination of the present disclosure can be 500, 750 or 1000 milligrams. Further optionally, the unit dosage strength of sitagliptin free base anhydrate (active moiety) for inclusion into the fixed-dose combination pharmaceutical compositions of the present disclosure can be 25, 50, or 100 milligrams. An equivalent amount of sitagliptin phosphate monohydrate to the sitagliptin free base anhydrate used in the pharmaceutical compositions can correspondingly be 32.125, 64.25 or 128.5 milligrams.

(51) According to some other embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of an SGLT-2 inhibitor (e.g. dapagliflozin) or a pharmaceutically acceptable salt thereof. One particular solid dosage form as such relates to tablets comprising a fixed-dose combination of a controlled-release form of metformin hydrochloride coated with an immediate-release form dapagliflozin. Optionally, the unit dosage strength of the metformin hydrochloride for incorporation into the fixed-dose combination of the present disclosure can be 500, 750 or 1000 milligrams, and the unit dosage strength of the dapagliflozin for incorporation into the fixed-dose combination of the present disclosure can be 2.5-10 mg.

(52) According to yet some other embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of a sulfonylurea (e.g. glipizide or glyburide) or a pharmaceutically acceptable salt thereof, such as glipizide or glyburide, and the unit dosage strength of the glipizide or glyburide for incorporation into the fixed dosage combination of the present disclosure can be 1.25-10 mg.

(53) According to yet some other embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of a meglitinide (e.g. repaglinide or nateoglinide) or a pharmaceutically acceptable salt thereof, such as repaglinide or nateoglinide, and the unit dosage strength of the repaglinide for incorporation into the fixed dosage combination of the present disclosure can be 0.5-5 mg; and the unit dosage strength of the nateoglinide for incorporation into the fixed dosage combination of the present disclosure can be 30-60 mg.

(54) According to yet some other embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of a thiazolidinedione (e.g. pioglitazone or rosiglitazone) or a pharmaceutically acceptable salt thereof. Herein, the unit dosage strength of the pioglitazone for incorporation into the fixed dosage combination of the present disclosure can be 15-45 mg, while the unit dosage strength of the rosiglitazone for incorporation into the fixed dosage combination of the present disclosure can be 1-4 mg.

(55) According to yet some other embodiments, the oral dosage form of the pharmaceutical composition comprises a fixed-dose combination of a controlled-release form of metformin or a pharmaceutically acceptable salt thereof and an immediate-release form of an alpha-glucosidase inhibitor (e.g. acarbose or miglitol) or a pharmaceutically acceptable salt thereof. For example, the unit dosage strength of the acarbose for incorporation into the fixed dosage combination of the present disclosure can be 12.5-100 mg, while the unit dosage strength of the miglitol for incorporation into the fixed dosage combination of the present disclosure can be 12.5-100 mg.

(56) The following examples further describe and demonstrate embodiments within the scope of the present invention. These embodiments are given solely for the purpose of illustration and are not intended to be construed as limitations of the present disclosure as many variations thereof are possible without departing from the spirit and scope of the invention.

Embodiment 1

(57) This embodiment illustrates the preparation of an oral dosage form of the pharmaceutical composition, which substantially comprises an osmatic pump controlled release metformin hydrochloride (HCl) core tablet (i.e. core portion, 1000 mg composition) coated with an immediate-release (IR) sitagliptin phosphate film (i.e. outer portion, 100 mg composition).

(58) To be more specific, the cores of the controlled release metformin HCl membrane coated tablets were formulated by a fluid bed granulation, where hydroxypropyl cellulose (HPC-EF) was dissolved into water to make approximately 5% solids w/w HPC-EF solution, which was then sprayed on delumped metformin HCl, sorbitol and sodium lauryl sulfate.

(59) The dried granules were dried and milled through a co-mill 0.8 mm. Milled granules were blended with magnesium stearate for approximately 5 minutes at 25 RPM in a V-Blender. The granulation conditions for the core portions of the oral dosage form, i.e. metformin core tablets (shown as “metformin CR (controlled release)”) are summarized in Table 3.

(60) TABLE-US-00003 TABLE 3 Metformin ER Granulation Conditions Granulation Temperature (° C.) 45-55 Air Volume (HZ) 25-45 Atomization Air Pressure (Bar) 2-3 Fluid Bed Spray Rate (g/min)  5-10 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(61) The final blend was compressed on an automatic tablet press into tablets using 10.0×20.5 mm long tooling.

(62) The core tablets were then coated with a controlled membrane film by coating with a solution comprising CA-398-10 (i.e. polymer material for the controlled membrane film) and PEG 6000 (i.e. flux enhancer for the controlled membrane film) in acetone solution, followed by curing for 60 minutes at 50° C. The controlled membrane coating condition is summarized in Table 4.

(63) TABLE-US-00004 TABLE 4 Controlled Membrane Coating Conditions. Product Temperature (° C.) 15-30 Air Volume (HZ) 35 Atomization Air Pressure (Bar) 0.9 Spray Rate (g/min) 10-20 Pan Speed (rpm) 17-18 Inlet Temperature (° C.) 20-30

(64) The coated tablets were laser drilled two holes (e.g. one hole on each side of the tablet, as illustrated in FIG. 1), and each hole should be within ±5 mm of the middle of the tablet, the diameter of orifice should be between 0.40 to 0.60 mm, and the depth of orifice should be between 0.10 to 2.00 mm.

(65) The sitagliptin phosphate coating solution was prepared by mixing all the excipients and sitagliptin phosphate in the required amount of purified water using a suitable homogenizer until the solids were dissolved. The sitagliptin phosphate coating solution was prepared to a total of approximately 18.0% solids w/w, which was then applied onto the metformin coated tablets and the amount of solids deposited in the active pharmaceutical ingredient (“API”) film layer (i.e. the outer portion of the oral dosage) was controlled to achieve the desired sitagliptin dose.

(66) The membrane-coated metformin HCl controlled release core tablets were loaded into a suitable perforated side-vented coating pan with baffles fitted with single spray guns to produce a spray fan to cover the entire width of the tablet bed; the average weight of warmed uncoated tablet was determined as the initial starting weight; the sitagliptin phosphate coating suspension was sprayed onto the tablet bed at a suitable spray rate and atomization pressure; spraying with the sitagliptin phosphate coating suspension was continued while monitoring the tablet weight until the required weight gain was obtained; an approximate dried coat weight of 130 mg equivalent to 50 mg sitagliptin (as free base) or 260 mg equivalent to 100 mg of sitagliptin (as free base) was deposited over the tablet cores; spraying was stopped, and the tablets were dried and discharged from the coating pan. The sitagliptin film coating conditions are summarized in Table 5.

(67) TABLE-US-00005 TABLE 5 Sitagliptin Film Coating Conditions Product Temperature (° C.) 35-45 Air Volume (HZ) 35/45 Atomization Air Pressure (Bar)   1.0 Spray Rate (g/min)  9-10 Pan Speed (rpm) 15 Inlet Temperature (° C.) 55-65

(68) The Sitagliptin coated tablets were then coated with a seal coating solution, which is made of hypromellose and polyethylene glycol an Opadry material or other suitable water-soluble material by first dissolving the hypromellose and polyethylene glycol, preferably Opadry Clear (YS-1-7006) which is a mixture coating material with hypromellose and polyethylene glycol, in purified water. The Opadry coating solution was then sprayed onto the core tablets using a pan coater under the following conditions: exhaust air temperature of 38-42° C.; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The Opadry Clear of the coating constitutes about 20-25 mg/tablet.

(69) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (1000 mg) coated with immediate release sitagliptin phosphate outer film (100 mg)) obtained by the preparation method (i.e. EMBODIMENT 1) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 1000 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 100 mg composition) are summarized in Table 6 and Table 7, respectively.

(70) TABLE-US-00006 TABLE 6 Metformin HCl Controlled Release Tablet, 1000 mg Composition. Materials % w/w Metformin HCl 83.3 Sodium Lauryl Sulfate. 3.8 Sorbitol 5.2 HPC EF 5.1 Magnesium Stearate 0.8 Cellulose Acetate 1.7 Polyethylene glycol 0.25 Total 100.0

(71) TABLE-US-00007 TABLE 7 Sitagliptin Phosphate Film, 100 mg Composition. Materials % w/w Sitagliptin Phosphate (100 mg 52.05 Free base) HPMC E5 47.95 Total 100.0

Embodiment 2

(72) This embodiment illustrates the preparation of an oral dosage form of the pharmaceutical composition, which substantially comprises an osmatic pump controlled release metformin hydrochloride (HCl) core tablet (i.e. core portion, 1000 mg composition) coated with an immediate-release (IR) sitagliptin phosphate film (i.e. outer portion, 100 mg composition).

(73) To be more specific, the cores of the controlled release metformin HCl membrane coated tablets were formulated by a fluid bed granulation, where povidone (PVP-K90) was dissolved into water to make approximately 7% solids w/w PVP solution, which was then sprayed on delumped metformin HCl and sodium lauryl sulfate.

(74) The dried granules were dried and milled through a co-mill 0.8 mm. Milled granules were blended with magnesium stearate for approximately 5 minutes at 25 RPM in a V-Blender. The granulation conditions for the core portions of the oral dosage form, i.e. metformin core tablets (shown as “metformin CR (controlled release)”) are summarized in Table 8.

(75) TABLE-US-00008 TABLE 8 Metformin ER Granulation Conditions Granulation Temperature (° C.) 33-45 Air Volume (HZ) 25-45 Atomization Air Pressure (Bar) .sup. 2-2.5 Fluid Bed Spray Rate (g/min)  5-10 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(76) The final blend was compressed on an automatic tablet press into tablets using 12.0×12.0 mm round tooling for the 500 mg formulation and 10.0×20.5 mm long or 10.3×21.2 mm oval tooling for the 1000 mg formulation. The core tablets (i.e. the core portion of the oral dosage form) obtained thereby were then coated with a seal coating solution, which is made of hypromellose and polyethylene glycol or other suitable water-soluble material by first dissolving the hypromellose and polyethylene glycol, preferably Opadry Clear (YS-1-7006) which is a mixture coating material with hypromellose and polyethylene glycol, in purified water. The coating solution was then sprayed onto the core tablets using a pan coater under the following conditions: exhaust air temperature of 38-42° C.; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The Opadry Clear of the coating constitutes about 10-15 mg/tablet.

(77) The seal film coated tablets were then coated with a controlled membrane film by coating with a solution comprising CA-398-10 (i.e. polymer material for the controlled membrane film) and PEG 3350 (i.e. pore forming agent/plasticizing agent for the controlled membrane film) in acetone solution, followed by curing for 60 minutes at 50° C. The controlled membrane coating condition is summarized in Table 9.

(78) TABLE-US-00009 TABLE 9 Controlled Membrane Coating Conditions. Product Temperature (° C.) 18.4-24.8 Air Volume (HZ) 35 Atomization Air Pressure (Bar)   0.9 Spray Rate (g/min) 14.4-15.9 Pan Speed (rpm) 17-18 Inlet Temperature (° C.) 24.3-30.sup. 

(79) The coated tablets were laser drilled two holes (e.g. one hole on each side of the tablet, as illustrated in FIG. 1), and each hole should be within ±5 mm of the middle of the tablet, the diameter of orifice should be between 0.30 to 0.80 mm, and the depth of orifice should be between 0.10 to 2.00 mm.

(80) The sitagliptin phosphate coating solution was prepared by mixing all the excipients and sitagliptin phosphate in the required amount of purified water using a suitable homogenizer until the solids were dissolved. The sitagliptin phosphate coating solution was prepared to a total of approximately 18.0% solids w/w, which was then applied onto the metformin coated tablets and the amount of solids deposited in the active pharmaceutical ingredient (“API”) film layer (i.e. the outer portion of the oral dosage) was controlled to achieve the desired sitagliptin dose.

(81) The membrane-coated metformin HCl controlled release core tablets were loaded into a suitable perforated side-vented coating pan with baffles fitted with single spray guns to produce a spray fan to cover the entire width of the tablet bed; the average weight of warmed uncoated tablet was determined as the initial starting weight; the sitagliptin phosphate coating suspension was sprayed onto the tablet bed at a suitable spray rate and atomization pressure; spraying with the sitagliptin phosphate coating suspension was continued while monitoring the tablet weight until the required weight gain was obtained; an approximate dried coat weight of 130 mg equivalent to 50 mg sitagliptin (as free base) or 260 mg equivalent to 100 mg of sitagliptin (as free base) was deposited over the tablet cores; spraying was stopped, and the tablets were dried and discharged from the coating pan. The sitagliptin film coating conditions are summarized in Table 10.

(82) TABLE-US-00010 TABLE 10 Sitagliptin Film Coating Conditions Product Temperature (° C.) 37.4-45.0 Air Volume (HZ) 35/45 Atomization Air Pressure (Bar)   1.0 Spray Rate (g/min)  9-10 Pan Speed (rpm) 15 Inlet Temperature (° C.) 58.6-65.6

(83) The Sitagliptin coated tablets were then coated with a seal coating solution, which is made of hypromellose and polyethylene glycol an Opadry material or other suitable water-soluble material by first dissolving the hypromellose and polyethylene glycol, preferably Opadry Clear (YS-1-7006) which is a mixture coating material with hypromellose and polyethylene glycol, in purified water. The Opadry coating solution was then sprayed onto the core tablets using a pan coater under the following conditions: exhaust air temperature of 38-42° C.; atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The Opadry Clear of the coating constitutes about 20-25 mg/tablet.

(84) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (1000 mg) coated with immediate release sitagliptin phosphate outer film (100 mg)) obtained by the preparation method (i.e. EMBODIMENT 2) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 1000 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 100 mg composition) are summarized in Table 11 and Table 12, respectively.

(85) TABLE-US-00011 TABLE 11 Metformin HCl Controlled Release Tablet, 1000 mg Composition. Materials % w/w Metformin HCl 84.7 Sodium Lauryl Sulfate. 4.2 Povidone K90 6.8 Magnesium Stearate 0.4 Hypromellose 1.4 Polyethylene glycol 0.6 Cellulose Acetate 1.7 Polyethylene glycol 0.2 Total 100.0

(86) TABLE-US-00012 TABLE 12 Sitagliptin Phosphate Film, 100 mg Composition. Materials % w/w Sitagliptin Phosphate (100 mg 52.05 Free base) HPMC E5 47.95 Total 100.0

Embodiment 3

(87) This embodiment illustrates the preparation of osmatic pump controlled-release (CR) metformin HCl core tablet (1000 mg composition) coated with an immediate-release (IR) sitagliptin phosphate film (50 mg composition).

(88) The procedures used were similar to, and can therefore reference to, EMBODIMENT 2 as described above, with certain variations. More specifically, the metformin CR granulation conditions, the controlled membrane coating conditions, and the sitagliptin film coating conditions are summarized in Table 13, Table 14, and Table 15, respectively.

(89) TABLE-US-00013 TABLE 13 Metformin CR Granulation Conditions. Granulation Temperature (° C.) 33-45 Air Volume (HZ) 25-45 Atomization Air Pressure (Bar) .sup. 2-2.5 Fluid Bed Spray Rate (g/min)  5-10 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(90) TABLE-US-00014 TABLE 14 Controlled Membrane Coating Conditions. Product Temperature (° C.) 18.4-24.8 Air Volume (HZ) 35 Atomization Air Pressure (Bar)   0.9 Spray Rate (g/min) 14.4-15.9 Pan Speed (rpm) 17-18 Inlet Temperature (° C.) 24.3-30.sup. 

(91) TABLE-US-00015 TABLE 15 Sitagliptin Film Coating Conditions. Product Temperature (° C.) 37.6-42.0 Air Volume (HZ) 25/40 Atomization Air Pressure (Bar)   1.0 Spray Rate (g/min) .sup. 7-8.8 Pan Speed (rpm) 15 Inlet Temperature (° C.) 64.4-65.2

(92) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (1000 mg) coated with immediate release sitagliptin phosphate outer film (50 mg)) obtained by the preparation method (i.e. EMBODIMENT 3) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 1000 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 50 mg composition) are summarized in Table 16 and Table 17, respectively.

(93) TABLE-US-00016 TABLE 16 Metformin HCl ER Tablet, 1000 mg Composition. Materials % w/w Metformin HCl 84.7 Sodium Lauryl Sulfate. 4.2 Povidone K90 6.8 Magnesium Stearate 0.4 Hypromellose 1.4 Polyethylene glycol 0.6 Cellulose Acetate 1.7 Polyethylene glycol 0.2 Total 100.0

(94) TABLE-US-00017 TABLE 17 Sitagliptin Phosphate Film, 50 mg Composition. Materials % w/w Sitagliptin Phosphate (50 mg Free base) 52.05 HPMC E5 47.95 Total 100.0

Embodiment 4

(95) This embodiment illustrates the preparation of osmatic pump controlled-release (CR) metformin HCl tablet (500 mg composition) coated with an immediate-release (IR) sitagliptin phosphate film (50 mg composition).

(96) The procedures used were similar to, and can therefore reference to, EMBODIMENT 2 as described above, with certain variations. More specifically, the metformin CR granulation conditions, the controlled membrane coating conditions, and the sitagliptin film coating conditions are summarized in Table 18, Table 19, and Table 20, respectively.

(97) TABLE-US-00018 TABLE 18 Metformin CR Granulation Conditions. Granulation Temperature (° C.) 33.7-45.4 Air Volume (HZ) 25-35 Atomization Air Pressure (Bar) .sup. 2-2.5 Fluid Bed Spray Rate (g/min) 7.54 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(98) TABLE-US-00019 TABLE 19 Controlled Membrane Coating Conditions. Product Temperature (° C.) 17.8-23.4 Air Volume (HZ) 35 Atomization Air Pressure (Bar) 0.9 Spray Rate (g/min) 14.5 Pan Speed (rpm) 19 Inlet Temperature (° C.) 22.1-38.0

(99) TABLE-US-00020 TABLE 20 Sitagliptin Film Coating Conditions. Product Temperature (° C.) 36.8-46.5 Air Volume (HZ) 35/43 Atomization Air Pressure (Bar) 0.9 Spray Rate (g/min) 9.51 Pan Speed (rpm) 15 Inlet Temperature (° C.) 64.6-65.9

(100) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (500 mg) coated with immediate release sitagliptin phosphate outer film (50 mg)) obtained by the preparation method (i.e. EMBODIMENT 4) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 500 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 50 mg composition) are summarized in Table 21 and Table 22, respectively.

(101) TABLE-US-00021 TABLE 21 Metformin HCl CR Tablet, 500 mg Composition. Materials % w/w Metformin HCl 82.5 Sodium Lauryl Sulfate. 4.1 Povidone K90 6.6 Magnesium Stearate 0.4 Hypromellose 1.3 Polyethylene glycol 0.6 Cellulose Acetate 4.0 Polyethylene glycol 0.5 Total 100.0

(102) TABLE-US-00022 TABLE 22 Sitagliptin Phosphate Film, 50 mg Composition. Materials % w/w Sitagliptin Phosphate (50 mg Free base) 52.05 HPMC E5 47.95 Total 100.0

Embodiment 5

(103) This embodiment illustrates the preparation of osmatic pump controlled-release (CR) metformin HCl tablet (1000 mg composition) coated with an immediate-release (IR) Sitagliptin phosphate film (100 mg composition).

(104) The procedures used were similar to, and can therefore reference to, EMBODIMENT 1 as described above, with certain variations. More specifically, the metformin CR granulation conditions, the controlled membrane coating conditions, and the sitagliptin phosphate film coating conditions are summarized in Table 23, Table 24, and Table 25, respectively.

(105) TABLE-US-00023 TABLE 23 Metformin CR Granulation Conditions. Granulation Temperature (° C.) 33-45 Air Volume (HZ) 25-45 Atomization Air Pressure (Bar) .sup. 2-2.5 Fluid Bed Spray Rate (g/min)  5-10 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(106) TABLE-US-00024 TABLE 24 Controlled Membrane Coating Conditions. Product Temperature (° C.) 18.4-24.8 Air Volume (HZ) 35   Atomization Air Pressure (Bar) 0.9 Spray Rate (g/min) 14.4-15.9 Pan Speed (rpm) 17-18 Inlet Temperature (° C.) 24.3-30.sup. 

(107) TABLE-US-00025 TABLE 25 Sitagliptin Film Coating Conditions. Product Temperature (° C.) 39.2-49.2 Air Volume (HZ) 25/40 Atomization Air Pressure (Bar) 1.0 Spray Rate (g/min) 4.64 Pan Speed (rpm) 15 Inlet Temperature (° C.) 64.8-65.2

(108) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (1000 mg) coated with immediate release sitagliptin phosphate outer film (100 mg)) obtained by the preparation method (i.e. EMBODIMENT 5) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 1000 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 100 mg composition) are summarized in Table 26 and Table 27, respectively.

(109) TABLE-US-00026 TABLE 26 Metformin HCl CR Tablet, 1000 mg Composition. Materials % w/w Metformin HCl 84.7 Sodium Lauryl Sulfate. 4.2 Povidone K90 6.8 Magnesium Stearate 0.4 Hypromellose 1.4 Polyethylene glycol 0.6 Cellulose Acetate 1.7 Polyethylene glycol 0.2 Total 100.0

(110) TABLE-US-00027 TABLE 27 Sitagliptin Phosphate Film, 100 mg Composition. Materials % w/w Sitagliptin Phosphate (100 mg Free base) 61.19 HPMC E5 31.19 PEG 3350 7.62 Total 100.0

Embodiment 6

(111) This embodiment illustrates the preparation of osmatic pump controlled-release (CR) metformin HCl tablet (1000 mg composition) coated with an immediate-release (IR) sitagliptin phosphate film (100 mg composition).

(112) The procedures used were similar to, and can therefore reference to, EMBODIMENT 1 as described above, with certain variations. More specifically, the metformin CR granulation conditions, the controlled membrane coating conditions, and the sitagliptin phosphate film coating conditions are summarized in Table 28, Table 29, and Table 30, respectively.

(113) TABLE-US-00028 TABLE 28 Metformin CR Granulation Conditions. Granulation Temperature (° C.) 33-45 Air Volume (HZ) 25-45 Atomization Air Pressure (Bar) .sup. 2-2.5 Fluid Bed Spray Rate (g/min)  5-10 Note: The LOD % of the granules after drying was NMT 3% as determine by moisture balance., where the term LOD is short for “Loss On Dry”, and the term NMT for “No More Than”.

(114) TABLE-US-00029 TABLE 29 Controlled Membrane Coating Conditions Product Temperature (° C.) 18.4-24.8 Air Volume (HZ) 35   Atomization Air Pressure (Bar) 0.9 Spray Rate (g/min) 14.4-15.9 Pan Speed (rpm) 17-18 Inlet Temperature (° C.) 24.3-30.sup. 

(115) TABLE-US-00030 TABLE 30 Sitagliptin Film Coating Conditions Product Temperature (° C.) 40.8-47.4 Air Volume (rpm) 25/40 HZ Atomization Air Pressure (Bar)   1.2 Spray Rate (g/min) 2.82-5.20 Pan Speed (rpm) 19 Inlet Temperature (° C.) 64.8-68.0

(116) In the oral dosage form (i.e. Metformin HCl controlled release core tablet (1000 mg) coated with immediate release sitagliptin phosphate outer film (100 mg)) obtained by the preparation method (i.e. EMBODIMENT 6) as described above, the various compositions for the core portion (i.e. metformin HCl controlled release tablet, 1000 mg composition) and for the outer portion (i.e. the sitagliptin phosphate film, 100 mg composition) are summarized in Table 31 and Table 32, respectively.

(117) TABLE-US-00031 TABLE 31 Metformin HCl CR Tablet, 1000 mg Composition Materials % w/w Metformin HCl 84.7 Sodium Lauryl Sulfate. 4.2 Povidone K90 6.8 Magnesium Stearate 0.4 Hypromellose 1.4 Polyethylene glycol 0.6 Cellulose Acetate 1.7 Polyethylene glycol 0.2 Total 100.0

(118) TABLE-US-00032 TABLE 32 Sitagliptin Phosphate Film, 100 mg Composition Materials % w/w Sitagliptin Phosphate (100 mg Free base) 61.19 Povidone K90 20.24 PEG 3350 18.57 Total 100.0

(119) In the following, the in vitro dissolution profiles for metformin HCl and sitagliptin phosphate and the in vivo plasma bioavailability for metformin of certain embodiments of the oral dosage form of the antidiabetic pharmaceutical compositions are examined.

(120) FIGS. 2A and 2B respectively show the in vitro dissolution profiles of metformin HCl and sitagliptin phosphate in the Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure. The in vitro dissolution test of the Metformin HCl was performed in a pH 6.8 buffer, as measured by USP Apparatus Type II at 50 rpm at 37° C., and the in vitro dissolution test of the sitagliptin phosphate was performed in a 0.025 mol/mL sodium chloride solution, as measured by USP Apparatus Type I at 75 rpm at 37° C. As shown in FIG. 2B, sitagliptin phosphate dissolves very quickly in the NaCl solution, with 29% dissolved at approximately 10 min, and almost fully dissolved after 60 min, thereby realizing an immediate release in the oral dosage form. As further shown in FIG. 2A, metformin HCl dissolves much slower compared with sitagliptin phosphate, with 30-40% dissolved at approximately 4 hr, 55-85% dissolved at approximately 8 hr, and almost fully dissolved after approximately 16 hr.

(121) Furthermore, the in vitro dissolution profiles for metformin HCl and sitagliptin phosphate in each of the above mentioned embodiments of the oral dosage form of the pharmaceutical composition are respectively determined and further compared with the dissolution profile of certain known antidiabetic prescription medicines (Janumet XR 1000 mg, Fortamet 500 mg, and Fortamet 1000 mg) as references.

(122) Herein Janumet XR is the brand name for sitagliptin phosphate and metformin hydrochloride extended-release tablets, which is an antidiabetic prescription medicine that contains sitagliptin phosphate (JANUVIA®) and extended-release metformin HCl. Fortamet is the brand name for metformin HCl tablets, which is an antidiabetic prescription medicine that contains either 500 mg or 1000 mg metformin HCl.

(123) The dissolution profiles are determined under the following conditions:

(124) Dissolution Medium: 900 ml, United State Pharmacopeia Phosphate buffer pH 6.8, refer United State Pharmacopeia for the detail procedures of preparation.

(125) Dissolution Method: United State Pharmacopeia Dissolution Test Device Type 1 Apparatus (Basket method), 100 rpm at 37° C.

(126) Detection Method: the High Performance Liquid Chromatography method is developed and used to measure the dissolved Metformin HCl and Sitagliptin Phosphate in the collected samples in the tested time points.

(127) The following tables (i.e. Table 33 and Table 34) respectively shows the dissolution results for sitagliptin phosphate and metformin HCl in the six embodiments of the oral dosage form described above and in the three known antidiabetic prescription medicines (Janumet XR 1000 mg, Fortamet 500 mg, and Fortamet 1000 mg).

(128) TABLE-US-00033 TABLE 33 Sitagliptin Phosphate Dissolution Result. EMBODI- EMBODI- EMBODI- EMBODI- EMBODI- EMBODI- Janumet Time MENT 1 MENT 2 MENT 3 MENT 4 MENT 5 MENT 6 XR (min) (100 mg)* (100 mg)* (50 mg)* (50 mg)* (100 mg)* (100 mg)* 1000 mg 10 29 28 60 39 32 64 26 15 39 38 78 51 49 90 55 30 64 62 98 73 92 97 81 60 91 89 100 96 103 98 96 Note: *the free base weight of sitagliptin phosphate

(129) TABLE-US-00034 TABLE 34 Metformin HCl CR Tablets Dissolution Result. Time EMBODIMENT EMBODIMENT EMBODIMENT EMBODIMENT (hrs) 1 (1000 mg) 2 (1000 mg) 3 (1000 mg) 4 (500 mg) 1 6  6 13 4 2 16 19 27 16 4 34 41 54 31 6 50 N/A 81 55 8 63 75 92 75 10 75 N/A 97 96 12 84 90 99 99 16 92 98 101 99 Janumet Time EMBODIMENT EMBODIMENT XR Fortamet Fortamet (hrs) 5 (1000 mg) 6 (1000 mg) 1000 mg 500 mg 1000 mg 1  5 12 25 7 8 2 23 25 46 19 18 4 50 55 68 36 38 6 N/A N/A 83 51 66 8 73 84 94 73 85 10 N/A N/A 101 86 91 12 92 93 104 94 96 16 96 96 104 99 99 Note: * the free base weight of metformin

(130) The in vivo plasma bioavailability for metformin of one embodiment (Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure, i.e., “test formulation”) of the oral dosage form of the antidiabetic pharmaceutical compositions in subjects under fasting or fed conditions is also examined and compared with the in vivo plasma bioavailability of one known antidiabetic prescription medicine (Fortamet 1000 mg, i.e., “reference formulation”), which is used as reference control.

(131) Specifically, the plasma concentration of metformin provided in EMBODIMENT 1 (formulation T) and the known antidiabetic prescription medicine (formulation R) was determined at different time points (0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 14.0, 16.0, 16.0, 20.0, 24.0, 28.0 and 36.0 hours) after the oral dosage form is orally administered to several subjects. The metformin plasma concentration results under fasting condition are summarized in Table 35 and Table 36, respectively.

(132) It is noted that the plasma concentration of metformin is in the unit of ng/ml; each of the highlighted values (i.e. values in bold and underlined font) in the two tables indicates the maximum plasma concentration (T.sub.max) of metformin for each subject after oral administration of a single dose of the oral dosage form of formulation T or formulation R; and the time point 0 represents the predose concentration of metformin.

(133) TABLE-US-00035 TABLE 35 Plasma concentration (ng/ml) profiles of the metformin determined at different time points after a single dose of the reference formulation is orally administered to different subjects under fasting condition. Time Subject ID No. (hr) 2 4 6 7 8 9 10 11 12 13 14 Mean CV % 0  0.0  0.0   0.0  0.0  0.0  0.0  0.0   0.0  0.0   0.0  0.0  0.0 — 2.0  88.7 231.3  142.7  65.2  43.4 106.4  92.0  64.7  36.3  94.0  63.3  93.5 58.5 3.0 254.0 220.7  309.6 146.0 136.3 286.2 117.1  193.2  81.6  216.7 175.7 194.3 36.8 4.0 445.0 242.3  589.9 179.7 215.0 333.7 224.4  476.6 129.3  354.2 271.4 314.7 44.8 4.5 393.1 254.4  934.5 203.7 350.1 470.4 227.1  591.8 145.2  470.6 312.3 395.7 56.3 5.0 428.2 364.4 1222.5 211.5 437.6 640.3 242.4  709.2 154.7 1064.2 300.3 525.0 66.9 5.5 413.4 355.0 1473.6 263.7 441.0 715.3 234.6  732.5 209.0 1063.1 379.5 571.0 69.3 6.0 599.1 407.1 1742.1 292.6 477.3 702.8 259.1  752.2 215.9 1309.4 404.7 651.1 73.0 6.5 781.8 481.4 1647.4 334.3 574.2 734.0 324.9  840.5 277.0 1496.6 486.0 725.3 63.4 7.0 793.3 540.9 1713.5 333.6 626.0 731.5 378.1 1018.2 318.1 1612.0 508.1 779.4 62.2 7.5 966.5 574.1 1687.3 384.3 635.5 834.0 415.7 1106.8 561.7 1623.1 624.0 855.7 52.8 8.0 943.5 608.7 1482.2 512.1 697.6 841.2 489.7 1167.1 683.7 1555.8 650.0 875.6 42.6 8.5 1088.7  642.4 1479.4 557.1 724.2 785.5 516.3 1276.4 741.7 1383.5 725.2 901.9 38.1 9.0 1070.0  584.1 1354.2 588.5 679.1 763.4 484.2 1331.2 700.6 1251.2 781.8 871.7 36.8 9.5 1021.5  559.3 1267.3 598.0 772.1 813.7 468.3 1227.5 833.2 1158.0 821.0 867.3 31.4 10.0 1168.7  585.5 1106.7 720.5 752.8 807.7 527.7 1174.8 827.6 1246.8 881.1 890.9 27.8 10.5 1199.8  643.0 1118.9 989.0 803.0 859.0 522.7 1214.6 845.7 1247.9 940.2 944.0 25.3 11.0 1235.8  689.8  911.2 1137.8  750.3 895.4 565.9 1279.5 846.3 1244.2 1055.0  964.7 25.2 11.5 1257.6  866.8  861.8 1161.4  769.6 972.0 596.6 1252.5 827.3 1151.6 1097.5  983.1 22.0 12.0 1275.7  886.4  811.5 1282.6  775.4 897.9 587.1 1222.9 752.2 1093.1 1180.9  978.7 24.7 14.0 1183.2  627.1  484.5 1343.0  646.9 547.0 646.0  616.9 492.0  603.6 912.3 736.6 38.8 16.0 911.3 377.3  302.2 1118.5  548.9 446.1 626.8  337.6 402.5  371.0 634.4 552.4 46.8 20.0 402.9 166.4  146.6 686.9 346.8 188.8 692.1  202.2 180.0  186.3 421.0 329.1 61.7 24.0 164.5  86.6  81.0 281.7 240.0  71.6 442.7  88.0 119.6  89.7 189.8 168.6 68.2 28.0  69.2  43.2  36.3 133.5 108.9  37.0 209.0  44.2 103.4  58.4  76.7  83.6 63.0 36.0  0.0  21.1   0.0  29.1  22.7  0.0  46.9   0.0  29.6  29.0  28.8  18.8 86.5

(134) TABLE-US-00036 TABLE 36 Plasma concentration (ng/ml) profiles of the metformin determined at different time points after a single dose of the test formulation is orally administered to different subjects under fasting condition. Time Subject ID No. (hr) 2 4 6 7 8 9 10 11 12 13 14 Mean CV % 0  0.0  0.0  0.0  0.0  0.0  0.0  0.0  0.0  0.0  0.0  0.0  0.0 — 2.0 132.3 143.0 127.0  83.5  87.0  82.9 105.1  93.4  52.4  89.7 103.4 100.0 26.1 3.0 310.2 227.7 237.4 119.0 166.0 182.3 185.7 234.3 101.1 175.5 208.2 195.2 29.8 4.0 429.4 222.4 331.0 169.6 226.2 212.0 236.9 330.7 162.8 270.6 412.1 273.1 33.4 4.5 460.0 193.2 369.5 185.9 265.6 244.7 301.1 355.5 183.1 327.2 374.2 296.4 30.6 5.0 633.4 197.4 417.8 214.7 327.9 305.8 348.1 372.0 274.4 489.0 342.6 356.6 34.8 5.5 769.6 241.8 512.3 290.2 353.8 325.6 503.7 478.5 273.1 668.0 373.4 435.4 38.8 6.0 844.7 273.9 588.8 377.0 390.9 383.3 537.2 513.9 306.9 800.2 446.0 496.6 37.7 6.5 872.2 271.4 733.3 475.8 413.1 449.3 639.7 563.7 480.2 890.6 479.4 569.9 34.2 7.0 933.6 290.3 838.0 487.4 391.7 488.1 670.0 630.5 604.6 882.3 580.9 617.9 33.0 7.5 895.6 309.9 907.3 537.5 410.9 462.1 725.3 789.2 716.1 817.1 635.6 655.2 30.7 8.0 938.1 340.2 922.0 597.6 430.4 507.4 744.4 990.0 692.4 917.4 701.1 707.4 31.3 8.5 983.4 354.4 1103.0  651.8 452.0 568.2 751.1 1075.0  782.8 662.7 746.4 739.2 32.6 9.0 920.7 367.9 1083.3  591.2 509.2 584.1 674.5 1034.8  1112.9  680.5 818.8 761.6 32.8 9.5 960.0 355.4 1152.4  648.7 510.6 587.4 723.6 1001.0  1152.1  663.7 885.6 785.5 33.5 10.0 905.4 422.3 1151.2  661.9 478.6 665.7 715.8 935.8 633.3 578.0 975.0 738.5 30.6 10.5 1033.8  547.9 1173.0  852.5 514.8 827.8 720.4 903.1 712.7 496.9 924.7 791.6 27.5 11.0 1153.0  543.0 1325.6  884.3 530.8 958.2 741.8 800.5 810.4 541.8 957.1 840.6 30.3 11.5 1044.4  568.5 1310.8  959.6 537.1 1007.6  884.5 760.6 875.3 411.3 986.1 849.6 30.8 12.0 1126.6  566.1 1260.8  1051.8  631.7 1031.7  882.7 728.5 962.5 438.3 1029.5  882.8 29.2 14.0 1000.9  404.4 896.8 1125.5  619.3 803.8 955.7 388.7 696.1 250.2 777.7 719.9 38.8 16.0 713.3 256.2 593.1 1032.5  537.2 627.3 842.8 240.1 541.5 184.8 619.3 562.6 46.1 20.0 314.8 113.8 271.6 603.8 485.9 290.3 392.5 133.9 308.2 140.2 372.5 311.6 48.5 24.0 173.0  69.1 117.9 299.9 310.0 112.1 240.3  68.5 203.5  93.0 229.7 174.3 50.8 28.0  78.0  31.4  52.4 191.3 107.5  42.8 112.3  29.6 123.9  53.1 106.4  84.4 58.5 36.0  24.2  0.0  0.0  44.3  25.8  0.0  26.0  0.0  39.0  20.6  27.7  18.9 86.8

(135) As shown in Table 36, the maximum plasma concentration (T.sub.max) of metformin for each subject after oral administration of a single dose of the oral dosage form of formulation T ranges approximately 8.5-14 hours among different subjects after oral administration, with the mean plasma concentration peaking at 12 hours after oral administration.

(136) Furthermore, the key pharmacokinetics (PK) parameters for formulation T after oral administration is further summarized in Table 37.

(137) TABLE-US-00037 TABLE 37 Pharmacokinetics (PK) parameters for formulation T. PK Parameters (Units) Test product (T) C.sub.max (ng/mL) 996.888 ± 225.0124 (22.57%) .sup.#T.sub.max (hr) 12.0 (8.5-14.0) AUC.sub.0-t (hr*ng/mL) 12070.934 ± 3098.2367 (25.67%) AUC.sub.0-∞ (hr*ng/mL) 12262.470 ± 3115.0755 (25.40%) t.sub.1/2 (hr) 4.087 ± 0.8083 (19.78%) K.sub.el (1/hr) 0.1753 ± 0.03237 (18.47%) AUC_% Extrap_obs (%) 1.643 ± 0.5687 (34.61%) Note: .sup.#For T.sub.max median (min-max)

(138) The mean plasma concentrations of metformin between the test formulation and the reference formulation are further compared.

(139) FIGS. 3A and 3B respectively show the linear and semi-logarithmic plots of mean plasma concentrations of metformin HCl versus time for the reference formulation (“Reference”) and the test formulation (“Test”, i.e., Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure) in subjects under fasting condition.

(140) FIGS. 4A and 4B respectively show the linear and semi-logarithmic plots of mean plasma concentrations of metformin HCl versus time for the reference formulation (“Reference”) and the test formulation (“Test”, i.e., Metformin HCl/Sitagliptin phosphate CR 1000/100 mg tablets formulation provided in Embodiment 1 of this present disclosure) in subjects under fed condition.

(141) It should be noted that these above embodiments and examples of the pharmaceutical composition comprising metformin HCl and sitagliptin phosphate serve as illustrating examples only and shall not be interpreted as limitations of the scope.

(142) All references cited in the present disclosure are incorporated by reference in their entirety. Although specific embodiments have been described above in detail, the description is merely for purposes of illustration. It should be appreciated, therefore, that many aspects described above are not intended as required or essential elements unless explicitly stated otherwise.

(143) Various modifications of, and equivalent acts corresponding to, the disclosed aspects of the exemplary embodiments, in addition to those described above, can be made by a person of ordinary skill in the art, having the benefit of the present disclosure, without departing from the spirit and scope of the disclosure defined in the following claims, the scope of which is to be accorded the broadest interpretation so as to encompass such modifications and equivalent structures.