WO2014193528A1

WO2014193528A1 - Amorphous dosage forms and methods

Info

Publication number: WO2014193528A1
Application number: PCT/US2014/031785
Authority: WO
Inventors: Dong Yang; Jie Cao
Original assignee: Anovel Pharmaceuticals, Llc
Priority date: 2013-04-29
Filing date: 2014-03-25
Publication date: 2014-12-04

Abstract

The current invention discloses amorphous dosage forms of pharmaceutical compounds and compositions, as well as the related methods. More particularly, the current invention teaches amorphous dosage forms of DPP4 inhibitors for diabetes therapeutics, as well as methods for the preparation of amorphous drug substance and converting them into oral solid dosage forms.

Description

AMORPHOUS DOSAGE FORMS AND METHODS

FIELD OF INVENTION

[0001] The current invention is related to amorphous dosage forms of pharmaceutical compounds, compositions, and the related methods. More particularly, the current invention teaches amorphous dosage forms of DPP4 inhibitors for diabetes therapeutics, as well as methods for the preparation of amorphous drug substance and converting them into oral solid dosage forms.

BACKGROUND OF INVENTION

[0002] In the pharmaceutical industry, about 60% of all new chemical entities (NCE) in development track include active ingredients that are poorly soluble in water. While

bioavailability has always been a concern in formulation development, there are several methods to improve bioavailability, such as micro-emulsion, particle size reduction, and amorphous drug substance. Amorphous form of drug substance refers to active pharmaceutical ingredient (API) molecules packed in a non-crystal form which provides higher bioavailability compared to that of crystal forms due to its low free energy, high dissolution rate and high saturation solubility. Because of these advantages, amorphous API has always been a focus on pharmaceutical research and product development.

[0003] A pure amorphous drug substance is unstable due to its low free energy (AG), and most likely it will convert to crystal form under exposure to moisture with time. To prevent or slow down this conversion, normally a high molecular weight pharmaceutical polymer, such as hydroxylpropyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP), will be used as crystallization inhibitor.

[0004] The enzyme DPP IV (dipeptidyl peptidase IV, or DPP 4), which is also known as CD26, is a serine protease that may lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having a proline or alanine residue at the N-terminal end. Therefore, DPP4 inhibitors interfere with the plasma level of bioactive peptides, including the peptide GLP-1, and perform as promising drugs for type II diabetes. Among the identified DPP 4 inhibitors are Vidagliptin, Saxagliptin, and Linagliptin.

[0005] In general, the basic structures for these DPP 4 inhibitors have been reported. For example, Vildagliptin has a chemical name of l-[[(5-hydroxy-2-adamantyl)amino]-acetyl]-2- cyano-, (S)-Pyrrolidine with a chemical structural formula (I) below.

(I)

[0006] Saxagliptin has a chemical name of (Is, 3s, 5s)-2[(2s)-2-amino-2-(3-hydroxyl-l- adamantyl)acetyl]-2-azabi-cyclo[3.1.0]hexane-3-carbomitrile with a chemical structural formula

(II) below.

(Π) [0007] Linagliptin has a chemical name of l-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2- butyn-l-yl)-8-(3-(R)-amino-piperidin-l-yl)-xanthine with a chemical structural formula (III) below.

(III)

[0008] However, previous reports failed to illustrate that the known DPP 4 inhibitors may be produced in a highly pure amorphous form. As indicated above, the amorphous form of pharmaceutical compounds in a composition may result in improved bioavailability and a better therapeutic outcome. The current invention provides DPP 4 inhibitor compounds and

compositions in amorphous forms without crystal forms.

[0009] In addition, using the DPP 4 inhibitors as examples, the current invention discloses a method to produce compounds and compositions in amorphous forms. More particularly, the current method discloses a convenient method which combines the conversion of crystal API into its stable amorphous form and the formation of a tablet dosage form in one step. The current method has a significant advantage over the above discussed methods.

[0010] There are several commonly used processing methods that may convert API crystal into its amorphous form. The processing methods include spray drying, vacuum/oven drying, freeze drying, and melt extrusion methods. A spray drying process usually consists of the steps of (1) preparing API with pharmaceutical a polymer solution and (2) conversion of resulting API- polymer solution into solid powder form by quickly removing the solvent using spray drying technology. Or, the resulting API-polymer solution may be loaded on a pharmaceutical excipient, such as microcrystalline cellulose, to convert to a solid powder using spray drying technology. Freeze drying may consist of the steps of (1) preparation of API with pharmaceutical excipient aqueous solution and (2) conversion of the resulting API-excipient solution into solid powder form by removing the solvent using freeze drying technology. Vacuum/oven drying is limited to laboratory scale preparation and isn't suitable for large scale manufacture. Melt extrusion is a non-solvent method to prepare amorphous API by extruding API crystal with suitable pharmaceutical polymer under high shear force and temperature. Due to the high process temperature, this technology may only be applied to a very limited number of drug substances because of the potential for drug substance degradation. Besides the disadvantages discussed above, all these methods require a secondary step to convert amorphous API into a final dosage form, such as a tablet and capsule.

[0011] However, previous reports failed to present a method that produces the known DPP 4 inhibitors in a highly pure amorphous form. As indicated above, the amorphous form of pharmaceutical compounds in a composition may result in improved bioavailability and a better therapeutic outcome. The current invention teaches a method fulfilling this need.

[0012] In summary, various compounds, compositions, and methods are known in the art.

However, as indicated above, they fail to teach amorphous form DPP 4 compounds and compositions. Moreover, the prior art methods are cumbersome and ineffective, failing to address all of the problems solved by the invention described herein. Various embodiments of this invention are herein illustrated and will be described in more detail below.

SUMMARY OF INVENTION

[0013] The present invention relates to stable pharmaceutical compositions comprising amorphous DPP IV inhibitors and how to prepare them. The term "DPP IV inhibitors" according to present invention refers to Vidagliptin, Saxagliptin, and Linagliptin free base and their salts, except when explicitly noted otherwise.

[0014] Further, the present invention relates to pharmaceutical compositions of amorphous DPP IV inhibitors, one or more pharmaceutical polymers, optionally a pH modifier, optionally one or more plasticizers, optionally one or more pharmaceutical fillers, such as microcrystalline cellulose, lactose, and mannitol. [0015] The present invention also relates to an amorphous film coating method to convert crystal API into its amorphous form and the related process to manufacture an oral tablet dosage form. The term "amorphous film coating" according to present invention refers to a film comprising API and a pharmaceutical polymer mixture in which API molecules exist in their amorphous form. The term "active pharmaceutical ingredient" (API) according to present invention refers to water soluble or water poorly soluble, basic or acidic, compounds, except when explicitly noted otherwise.

[0016] Also, amorphous API or amorphous API-polymer mixtures may be prepared by freeze- drying or spray-drying methods.

[0017] Further, the present invention relates to pharmaceutical composition of amorphous film coating comprising water soluble or water poorly soluble basic compounds, one or more pharmaceutical polymers, an organic/inorganic pH modifier, optionally one or more plasticizers, optionally one or more pharmaceutical fillers, such as microcrystalline cellulose, lactose, and mannitol.

[0018] Furthermore, the present invention relates to a pharmaceutical composition of amorphous film coated tablets dosage forms according to the invention.

[0019] According to some embodiments of the present invention, a processing method for preparation of amorphous film coated tablets comprises:

(1) a dissolving crystal API in a solvent with pharmaceutical polymer, optionally a pH modifier, optionally one plasticizer, optionally at least one pharmaceutical fillers, and optionally one antioxidant,

(2) coating the obtained solution on to an inert blank core tablet to form amorphous active coating layer (amorphous film coating) using a pan coater; and

(3) coating the resulting amorphous film coated tablets from Step (2) optionally with a seal coating layer, and followed by a color coating layer, and optionally a polish layer. [0020] Furthermore, the present invention relates to processes for preparing the pharmaceutical compositions according to some embodiments of the present invention. In one aspect, the process for preparing the pharmaceutical compositions comprises:

(4) in a solvent, dissolving or suspending DPP IV inhibitor(s), one or more pharmaceutical polymers, and optionally adjusting its pH value by a pH modifier, or optionally at least one plasticizers, optionally at least one pharmaceutical fillers, and optionally at least one antioxidant; and

(5) converting the solution or suspension provided in step (1) into a solid particulate form.

[0021] In some embodiments, the process for preparation of pharmaceutical composition according to present invention may comprise the following steps:

(6) in a solvent, dissolving or suspending DPP IV inhibitor(s), one or more pharmaceutical polymers, and optionally adjusting its pH value by a pH modifier, or optionally at least one plasticizers, optionally at least one pharmaceutical fillers, and optionally at least one antioxidant; and

(7) spray drying or oven drying (vacuum drying) the obtained solution or suspension to form a solid; and mixing the obtained solid with one or more pharmaceutically acceptable excipient (s) to prepare capsules or tablets.

[0022] Alternatively, the process for preparation of pharmaceutical composition according to some embodiments of the present invention may comprise the following steps:

(8) in a solvent, dissolving or suspending DPP IV inhibitor(s), one or more pharmaceutical polymers, and optionally adjusting its pH value by a pH modifier, or optionally at least one plasticizers, optionally at least one pharmaceutical fillers, and optionally at least one antioxidant; and

(9) coating the obtained solution or suspension on to an inert blank core tablet/or spherical blank pellets/beads to form amorphous active coating layer using pan coater or fluid bed coater; and (10) coating the resulting tablets or pellets/beads from Step (2) optionally with a layer of seal coating, followed by a color coating layer and a polish layer.

[0023] In addition, DPP-4 inhibitors may be used to prepare amorphous materials without combining with other polymers using the method below:

(11) dissolving DPP-4 inhibitors in a solvent, this solvent may be aqueous solution, such as water, water containing solutions.

(12) freeze-drying or spray drying the solution to form amorphous DPP-4 inhibitors.

[0024] In this application, active pharmaceutical ingredients (API) refer to water soluble or poor water soluble basic or acidic compounds, or their pharmaceutically acceptable salts thereof. The salt forms may be selected from any salt forms, such as but not limited to hydrochloride salt, maleate, fumarate, glcuronic acid salt, citrate, phosphate, and sulfate. The pH modifier may be any acid or base. The pH value of the resulting final solution may be between 1 and 10 depending on the type of API. For basic API, acids may be used as a pH modifier and the pH value is preferably from 1.0 to 7.0.

[0025] In this application, the term "DPP IV inhibitor" refers to Vidagliptin, Saxagliptin, and Linagliptin, or their pharmaceutically acceptable salts thereof. Thus, DPP IV inhibitors in this application may be their free base forms or their salt forms. The salt forms may be selected from any salt forms such as but not limited to hydrochloride salt, maleate, fumarate, glcuronic acid salt, citrate, phosphate, and sulfate. The pH modifier may be any acid or base and the pH value of the resulting final solution may be between 3 and 7, preferably 4.0 to 7.0.

[0026] Pharmaceutical polymers may be selected from the group consisting of

polyvinypyrrolidone (PVP) and/or derivatives, Kollidon VA64, polyvinyl alcohol (PVA), polyethylene glycol, hydroxylpropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (Na CMC), hydroxyethyl cellulose, and/or cellulose related derivatives, xanthan gums, pectins, alginates, Arabic gum and its derivatives, starch and its derivatives, dextrans and its derivatives, and other film forming polymers. Preferably, the pharmaceutical polymer is selected from Polyvinypyrrolidone (PVP) and/or derivatives, Kollidon VA64 and its related derivative, polyvinyl alcohol (PVA) and its related derivatives, and cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC), hyroxypropyl cellulose (HPC), and sodium carboxymethylcellulose (Na CMC). The ratio of DPP IV inhibitor to pharmaceutical polymers may be from 0.01 : 1.0 to 1.0: 0.1, and is more preferably from 0.1 :1.0 to 1.0:0.5.

[0027] The pH modifier may be any acid or base based on initial pH value of solution produced from selected DPP IV inhibitor. The acid may be an organic or an inorganic acid. The acid may, for example, be hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, citric acid, tartaric acid, hydroxybutanedioic acid, lactic acid, fumaric acid, maleic acid, succinic acid, glucuronic acid, salicylic acid, and/or mixtures of the same. Most preferably, the acid is citric acid, glucuronic acid, fumaric acid, hydrochloride acid, succinic acid, and/or mixtures of the same. The base may be organic or inorganic base. The base may be sodium hydroxide, potassium hydroxide, ammonium hydroxide, and/or amines and mixtures of the same.

[0028] The pharmaceutically acceptable plasticizers may be mono-, di-, or tri- saccharides, glycerin and/or its derivatives, polyethylene glycol and/or its related derivatives, citrate derivatives, propylene glycol and/or its derivatives, and/or mixtures of the same. Preferably, the plasticizer may be mono- and di-saccharides, polyethylene glycol and/or its related derivatives, and/or mixtures of the same.

[0029] The pharmaceutically acceptable solvent used in the preparation of DPP IV inhibitor solution or suspension may be selected from water, alcohol and/or their mixtures thereof. And, the alcohol may be selected from methanol, ethanol, isopropanol and/or mixture thereof.

Preferably, the solvent is water and/or ethanol, and/or a mixture of both.

[0030] The pharmaceutical fillers used in the preparation of DPP IV inhibitor solution or suspension may be water in-soluble or water soluble excipients. The filler may be

microcrystalline cellulose, mono and di-saccharides, such as lactose, mannitol, sorbitol, sucrose, and/or mixtures of the same and dibasic calcium phosphate and/or mixtures of the same, and/or mixture of two or more of them. [0031] The pharmaceutical antioxidant may be selected from the group consisting of tocopherols and its related derivatives, alkyl gallates and its related derivatives, ascorbic acid and its related derivatives, sodium thiosulfate, sodium metabisulphites, and/or mixtures of the same, .

[0032] The solid pharmaceutical composition of this invention preferably is suitable for oral application. The dosage form may be present in the form of tablets, pellets, capsules, powders, sachets, and lozenges. The most preferably dosage form is tablets and hard gelatin capsules.

[0033] For amorphous DPP IV inhibitor coated tablets and pellets formulation, the blank core tablets and pellets may be prepared with a pharmaceutical composition of common

pharmaceutical excipients which may form tablets and/or pellets. For blank core tablets, the composition preferably comprises at least one pharmaceutically commonly used filler, optionally at least one binder, optionally at least on glidant, optionally at least on disintegrant, and preferably at least one lubricant.

[0034] The pharmaceutical fillers may be selected from the group consisting of but no limited to polysaccharides, including microcrystalline cellulose and its related products, powdered cellulose, starch and its related products, and sugars, such as lactose, sucrose, mannitol, sorbitol, maltitol, xylitol, lactitol, saccharose, raffmose, trehalose, fructose, or mixture thereof, dibasic calcium phosphate, and/or their mixture thereof. Preferably, the fillers is selected from microcrystalline cellulose and its related materials, lactose, surcrose, mannitol, diabasic calucium phosphate., and/or their mixture thereof.

[0035] Pharmaceutical binders may be selected from the group consisting of but no limited to dry binders, such as microcrystalline cellulose and its related materials, starch and its related materials, cellulose derivatives, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and sodium carboxylmethyl cellulose (Na CMC), and/or the similar thereof, polyvinyl pyrrolidone (PVP), Kollidon VA64, gum acacia, polyethylene glycol and its derivatives, and/or mixture thereof. [0036] Pharmaceutical glidants may be selected from the group consisting of but not limited to talc, colloidal silicon dioxide, starch, magnesium stearate, and other long chain fatty acids and their insoluble salts, and/or mixtures of the same.

[0037] The pharmaceutical disintegrant may be selected from the group consisting of crospovidone, starch and its related derivatives, carboxymethylcellulose sodium,

microcrystalline cellulose, low substituted hydroxypropyl cellulose, and/or mixtures thereof. Preferably, the pharmaceutical composition comprises crospovidone as a disintegrant.

[0038] The lubricant may be selected from the group consisting of magnesium stearate, magnesium palmitate, stearic acid, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil and its derivatives, sodium stearyl fumarate, and/or mixtures thereof. Preferably, the pharmaceutical composition comprises magnesium stearate as lubricant.

[0039] For tyhe pellet core, the composition may comprise cellulose and its related materials, sugar, such as sucrose, lactose, mannitol, sorbitol and mixtures thereof, starch and its related materials, and/or mixtures thereof.

[0040] The pharmaceutical composition of an inner seal coating layer comprises at least one pharmaceutical polymer and optionally at least one pharmaceutical plasticizer, one anti-adherent agent or glidant, and opacifying agent dissolved or suspended in a solvent. The pharmaceutical polymer according to the present invention may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), ethyl cellulose (EC), metharylic polymers, preferably PVA and HPMC. The

pharmaceutical plasticizer according to the present invention may be selected from the group consisting of triacetin, diethyl phthalate, tributyl sebacate and polyethylene glycol (PEG), and preferably PEG. The anti-adherent agent or glidant may be selected from the group consisting of talc, fumed silica, magnesium stearate and/or mixtures of the same. Opacifying agent may include titanium dioxide. [0041] The pharmaceutical composition of a color coating layer may comprise coloring agent and/or pharmaceutical polymers. It may be selected from commercial available products such as Colorcon's Opadry® related products.

[0042] For amorphous DPP IV inhibitor containing capsules, direct compressed tablets, powders, sachets, and lozenges, the pharmaceutical composition according to this invention will comprise one or more additional excipients in addition to the amorphous DPP IV inhibitor preparation. The pharmaceutical compositions of capsule, direct compressed tablets, powders, sachets, and lozenges may comprise at least amorphous DPP IV inhibitor preparations, and/or with one or more suitable pharmaceutical excipients selected from but not limited to

pharmaceutical fillers/diluents, binders, disintegrants, glidants, lubricants, antioxidant and/or mixtures of the same as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 shows the Powder XRD Pattern of Original Vildagliptin Crystal.

[0044] Figure 2 shows the Powder XRD Pattern of Amorphous Vildagliptin Prepare in Example 1.

[0045] Figure 3 shows the Powder XRD Pattern of Amorphous Vildagliptin Prepared in Example 2.

[0046] Figure 4 shows the Powder XRD pattern of Amorphous Vildagliptin prepared from Example 3.

[0047] Figure 5 shows the Powder XRD Pattern of original Linagliptin crystal.

[0048] Figure 6 shows the Powder XRD Pattern of the amorphous Linagliptin prepared from Example 4.

[0049] Figure 7 shows the Dissolution profile of Vildagliptin direct compressed tablets prepared from Example 5. [0050] Figure 8 shows the Dissolution profile of amorphous Vildagliptin filmed coated tablet formulation from Example 6.

[0051] Figure 9 shows the Powder XRD Pattern of the original Saxagliptin free base.

[0052] Figure 10 shows the Powder XRD Pattern of the amorphous Saxagliptin prepared from Example 7.

DETAILED DESCRIPTION OF THE INVENTION

[0053] In this application, the term "amorphous API" refers to the polymer and API mixture in which API molecules are uniformly distributed without substantial crystal forms.

Examples

Example 1

[0054] Amorphous Vildagliptin preparation: Vildagliptin was dissolved in water and its pH value was adjusted by adding citric acid to 5.6. Then, HPMC E5 was added and dissolved by stirring to form clear solution. This solution was dried at 60°C in an oven for 12 hours. The resulting solid was then dried at 60°C for 3 hours under a vacuum. The doses are according to Table 1.

[0055] Original Vildagliptin crystal Powder XRD pattern was measured and shown in Figure 1. The Power XRD pattern of resulting amorphous solid was measured and shown in Figure 2.

Table 1. Composition of amorphous Vildagliptin preparation example 1

HPMC E5 5.0

Water 50.0

Example 2

[0056] Amorphous Vildagliptin preparation: Vildagliptin was dissolved in water and its pH value was adjusted by adding citric acid to 5.6. Then, PVP K30 was added and dissolved by stirring to form a clear solution. This solution was dried at 60°C in an oven for 12 hours. The doses are according to Table 2.

[0057] The resulting solid was then dried at 60°C for 3 hours under a vacuum. Powder XRD pattern was measured and is shown in Figure 3.

Table 2. Composition of amorphous Vildagliptin preparation example 2

Example 3 [0058] Amorphous Vildagliptin preparation: Vildagliptin was dissolved in water and its pH value was adjusted by adding citric acid to 5.6. Then, HPMC E5 was added and dissolved by stirring to form clear solution. Finally, Avicel PHI 02 was added to form a suspension. This solution was dried at 60°C in an oven for 12 hours. The resulting solid was then dried at 60°C for 3 hours under a vacuum. The doses are according to Table 3.

[0059] The Powder XRD pattern of resulting amorphous solid was measured and shown in Figure 4.

Table 3. Composition of amorphous Vildagliptin preparation example 3

[0060]

[0061] Example 4

[0062] Amorphous Linagliptin preparation: Linagliptin was suspended in water and then citric acid was added and mixed. After Linagliptin was totally dissolved, PVP K30 was added and dissolved with stirring to form a clear solution. This solution was dried at 60°C in an oven for 12 hours. The resulting solid was then dried at 60°C for 3 hours under a vacuum. The doses are according to Table 4. [0063] The Powder XRD pattern of original Linagliptin crystal was measured and shown in Figure 5. And, the Power XRD pattern of resulting amorphous solid was measured and shown in Figure 6.

[0064]

[0065] Table 4. Composition of amorphous Linagliptin preparation example 4

Example 5

[0066] lOOmg Amorphous Vildagliptin direct compressed tablet formulation: Spray dried or vacuum dried amorphous Vildagliptin with formula of Example 2 was mixed with filler, such as Avicel PHI 02, with glidant, such as Aerosil PH200, and with disintegrant, such as crospovidone, sieved, and then mixed again to form uniform mixture. Lubricant, such as Magnesium stearate, was added and blended to form final blend. This final blend was then compressed into tablet. Dissolution was performed in 900 ml of 0.01 N HC1 using USP apparatus II with a paddle speed of 50 rpm and temperature of 37.5 °C. The doses are according to Table 5.

[0067] The dissolution profile is shown in Figure 7.

Table 5. Composition o 100mg Amorphous Vildagliptin direct compressed tablet formulation Composition Percentage (%) Weight (mg) per unit

Amorphous Vildagliptin 45.2 226.0 (Example 2)

Avicel pH102 43.4 217.0

Aerosil PH200 0.40 2.00

Crospovidone 10.0 50.0

Magnesium stearate 1.0 5.00

Total 100.0 500.0

Example 6

[0068] 100 mg Amorphous Vildagliptin active coated tablet formulation: A solution of Vildagliptin with the composition of Example 2 was coated on blank core tablets prepared from Avicel pH102 and Mannitol DC as shown above with a pan coater. The weight of active coating layer was actually controlled based on the dose of DPP IV inhibitor. Dissolution was performed in 900 ml of 0.01 N HC1 using USP apparatus II with a paddle speed of 50 rpm and temperature of 37.5°C. The doses are according to Table 6.

[0069] The dissolution profile is shown in Figure 8.

Table 6. Composition of 100 mg Amorphous Vildagliptin film coated tablet formulation Composition Percentage (%) Weight (mg) per unit

Active coating Amorphous 43.0 226.0

layer Vildagliptin

(Example 2)

Avicel pH102 33.6 177.0

Blank core Mannitol DC 16.8 88.5

tablet

Aerosil PH200 0.29 1.50

Crospovidone 5.74 30.0

Magnesium 0.57 3.00

stearate

Total 100.0 526.0

Example 7

[0070] 1.0 gram Saxagliptin free base was dissolved in 10 ml of purified water and the pH was adjusted with citric acid to pH 6.3. Then, 2.0 gram of PVP K30 was dissolved in this solution with stirring. This mixture was dried in an oven at 50 °C for 12 hours. Power XRD diagram of the original Saxagliptin free base is shown in Figure 9. Power XRD diagram of the amorphous Saxagliptin collected after processing is shown Figure 10.

Table 7._omposition of amorphous Saxagliptin preparation in example 7

Citric acid 0.20

PVP K30 2.0

Water 5.00

[0071] It is understood that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.

Claims

What is Claimed:

1. A pharmaceutical composition comprising amorphous DPP IV inhibitors.

2. The pharmaceutical compositions of claim 1, further comprising:

a pharmaceutical polymer; and/or

a pH modifier, wherein

the amorphous DPP IV inhibitors are prepared by a method comprising the following steps:

(a) preparing a solution of the DPP IV inhibitor with pharmaceutical polymer and adjusting its pH from 2 to 7 with a pH modifier, and

(b) spraying dry the obtained solution into its solid powder form;

(c) loading the obtained solution on to pharmaceutical excipients by spray drying; or

(d) coating the obtained solution onto blank core tablets or blank core pellets.

3. The pharmaceutical composition of claim 2, wherein the method to prepare the pharmaceutical compositions according to claim 2 further comprises the following steps:

(a) mixing spraying dried amorphous DPP IV inhibitors in Claim 2 (b) and (c) with acceptable excipients to prepare pharmaceutical dosage forms, or

(b) seal coating and following by color coating and polish coating of amorphous DPP IV inhibitor coated blank core tablets or blank core pellets from (d).

4. The pharmaceutical composition of claim 2, wherein the DPP IV inhibitor is Sitagliptin, Vidagliptin, Saxagliptin, and Linagliptin free base or pharmaceutical salts, including citrate salts, phosphate salts, hydrochloride salts, sulfate salts, lactate salts, maleate salts, fumarate salts, glucuronic salts, salicylic salts, and tartrate salts.

5. The pharmaceutical composition of claim 2, wherein the pH modifier is an acid or a base, the acid is selected from the group of consisting hydrochloric acid, citric acid, sulfuric acid, glucuronic acid, maleic acid, lactic acid, tartrate acid, and salicylic acid, and the base is selected from the group of consisting sodium hydroxide, potassium hydroxide, ammonium hydroxide, and amine derivaties.

6. The pharmaceutical composition of claim 2, wherein the pharmaceutical polymer is selected from the group consisting of of polyvinylpyrrolidone (PVP) and its co-polymers or derivatives, cellulose related polymers and derivatives, polyvinyl alcohol and its related derivatives, and mixtures thereof.

7. The pharmaceutical composition of claim 2, wherein the pharmaceutical polymer is selected from the group consisting of but no limited to polyvinylpyrrolidone (PVP) and its copolymers and derivatives, cellulose related polymers and derivatives, and polyvinyl Alcohol, and mixtures thereof.

8. The pharmaceutical composition of claim 2, wherein the pharmaceutical solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, and mixtures thereof.

9. The pharmaceutical composition of claim 2, further comprising: a pharmaceutically acceptable plasticizers, wherein the pharmaceutically acceptable plasticizers is mono-, di-, or tri- saccharides, glycerin or its derivatives, polyethylene glycol and its related derivatives, citrate derivatives, propylene glycol or its derivatives, and mixtures of the same.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable plasticizers is mono- and di-saccharides, polyethylene glycol and its related derivatives, and mixtures of the same.

11. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, powder cellulose, mannitol, lactose, sucrose, and mixture thereof.

12. The pharmaceutical composition of claim 2, wherein the blank core tablet comprises:

(1) at least one pharmaceutical commonly used filler;

(2) at least one binder;

(3) at least one glidant;

(4) at least one disintegrant; and

(5) at least one lubricant.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical commonly used fillers is selected from the group consisting of polysaccharides, starch and its related products, and sugars or mixture thereof, dibasic calcium phosphate, and mixtures of the same.

14. The pharmaceutical composition of claim 12, wherein the pharmaceutical commonly used binder is selected from the group consisting of dry binders, starch and its related materials, cellulose derivatives, polyvinyl pyrrolidone (PVP), Kollidon VA64, gum acacia, polyethylene glycol or its derivatives, and mixtures of the same.

15. The pharmaceutical composition of claim 12, wherein the pharmaceutical glidant is selected from the group consisting of talc, colloidal silicon dioxide, starch, magnesium stearate, and other long chain fatty acids and their insoluble salts, and mixtures of the same.

16. The pharmaceutical composition of claim 12, wherein the pharmaceutical disintegrant is selected from the group consisting of crospovidone, starch and its related derivatives, carboxymethylcellulose sodium, microcrystalline cellulose, low substituted hydroxypropyl cellulose, and mixtures thereof.

17. The pharmaceutical composition of claim 12, wherein the pharmaceutical lubricant is selected from the group consisting of magnesium stearate, magnesium palmitate, stearic acid, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil or its derivatives, sodium stearyl fumarate, and mixtures thereof.

18. The pharmaceutical composition of claim 2, wherein the blank core tablet comprises: cellulose.

19. The pharmaceutical composition of claim 3, wherein the acceptable pharmaceutical excipients comprise at least pharmaceutical fillers, optionally, at least one binder; optionally, at least one glidant; optionally, at least one disintegrant; and at least one lubricant.

20. The pharmaceutical composition of claim 2, wherein the ratio of DPP IV inhibitors to pharmaceutical polymer and filler ranges from 0.01 : 1 to 1 :0.1.

21. A pharmaceutical process to convert crystal basic or acidic API into an amorphous film coated tablet dosage forms, the process comprising:

(a) dissolving crystal API in a solvent, pharmaceutical polymer, optionally a pH modifier, optionally one plasticizer, optionally at least one pharmaceutical fillers, and optionally one antioxidant, and

(b) coating the obtained solution on to an inert blank core tablet to form amorphous active coating layer (amorphous film coating) using a pan coater; and

(c) coating the resulting amorphous film coated tablets from Step (b) with a seal coating layer, and followed by a color coating layer, and optionally a polish layer.

22. The pharmaceutical process of claim 21, the pharmaceutical compositions of amorphous API coating layer comprises amorphous API, pharmaceutical polymer, optionally a pH modifier. The amorphous API coating layer is prepared by the processes that comprise the following steps:

(b) coating the above obtained solution onto blank core tablets using a pan coater.

23. The pharmaceutical process of claim 22, wherein the API in pharmaceutical composition refers to water soluble or water poorly soluble basic or acidic pharmaceutical active ingredients, or their pharmaceutical salts.

24. The pharmaceutical process of claim 22, wherein the pharmaceutical composition of active pharmaceutical ingredient to pharmaceutical polymer and filler ranges from 0.01 : 1 to 2: 1.

25. The pharmaceutical process of claim 22, wherein the pH modifier is selected from acids or bases, wherein acids is selected from the group of consisting hydrochloric acid, citric acid, sulfuric acid, glucuronic acid, maleic acid, lactic acid, tartrate acid, and salicylic acid, and the base is selected from the group of consisting sodium hydroxide, potassium hydroxide, ammonium hydroxide, and amine derivatives.

26. The pharmaceutical process of claim 22, wherein the Pharmaceutical polymer is selected from the group consisting of polyvinylpyrrolidone (PVP) and its co-polymers or derivatives, cellulose related polymers and derivatives, polyvinyl alcohol and its related derivatives, and mixtures thereof.

27. The pharmaceutical process of claim 22, wherein the pharmaceutical solvents is selected from the group consisting of water, methanol, ethanol, isopropanol, and mixtures thereof.

28. The pharmaceutical process of claim 22, wherein the pharmaceutically acceptable plasticizers is mono-, di-, or tri- saccharides, glycerin or its derivatives, polyethylene glycol orts related derivatives, citrate derivatives, propylene glycol or its derivatives, and mixtures of the same.

29. The pharmaceutical process of claim 28, wherein the pharmaceutically acceptable the plasticizer is mono- and di-saccharides, polyethylene glycol and its related derivatives, and mixtures of the same.

30. The pharmaceutical process of claim 22, wherein the pharmaceutically acceptable fillers is selected from the group consisting of microcrystalline cellulose, powder cellulose, mannitol, lactose, sucrose, and mixture thereof.

31. The pharmaceutical process of claim 22, wherein the blank core tablets comprises:

(1) at least one pharmaceutical commonly used filler;

(2) at least one binder;

(3) at least one glidant;

(4) at least one disintegrant; and

(5) at least one lubricant.

32. The pharmaceutical process of claim 22, wherein the pharmaceutical commonly used fillers is selected from the group consisting of polysaccharides, including microcrystalline cellulose and its related products, powdered cellulose, starch and its related products, dibasic calcium phosphate, and mixtures of the same.

33. The pharmaceutical process of claim 31, wherein the pharmaceutical commonly used binder is selected from the group consisting of dry binders, starch and its related materials, cellulose derivatives, polyvinyl pyrrolidone (PVP), Kollidon VA64, gum acacia, polyethylene glycol or its derivatives, and mixtures of the same.

34. The pharmaceutical process of claim 31, wherein the pharmaceutical glidant is selected from the group consisting talc, colloidal silicon dioxide, starch, magnesium stearate, and mixtures of the same.

35. The pharmaceutical process of claim 31, wherein the pharmaceutical disintegrant is selected from the group consisting of crospovidone, starch and its related derivatives, carboxymethylcellulose sodium, microcrystalline cellulose, low substituted hydroxypropyl cellulose, and mixtures thereof.

36. The pharmaceutical process of claim 31, wherein the pharmaceutical lubricant is selected from the group consisting of magnesium stearate, magnesium palmitate, stearic acid, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil or its derivatives, sodium stearyl fumarate, and mixtures thereof.