WO2014193528A1 - Préparations amorphes et méthodes associées - Google Patents

Préparations amorphes et méthodes associées Download PDF

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Publication number
WO2014193528A1
WO2014193528A1 PCT/US2014/031785 US2014031785W WO2014193528A1 WO 2014193528 A1 WO2014193528 A1 WO 2014193528A1 US 2014031785 W US2014031785 W US 2014031785W WO 2014193528 A1 WO2014193528 A1 WO 2014193528A1
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WIPO (PCT)
Prior art keywords
pharmaceutical
derivatives
mixtures
group
amorphous
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PCT/US2014/031785
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English (en)
Inventor
Dong Yang
Jie Cao
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Anovel Pharmaceuticals, Llc
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Publication of WO2014193528A1 publication Critical patent/WO2014193528A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • 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.
  • NCE new chemical entities
  • 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.
  • 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.
  • AG free energy
  • HPMC hydroxylpropyl methyl cellulose
  • PVP polyvinylpyrrolidone
  • DPP IV dipeptidyl peptidase IV, or DPP 4
  • CD26 dipeptidyl peptidase IV
  • DPP4 inhibitors interfere with the plasma level of bioactive peptides, including the peptide GLP-1, and perform as promising drugs for type II diabetes.
  • DPP 4 inhibitors are Vidagliptin, Saxagliptin, and Linagliptin.
  • 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
  • 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.
  • compositions in amorphous forms without crystal forms are provided.
  • 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.
  • 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.
  • 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.
  • the present invention relates to stable pharmaceutical compositions comprising amorphous DPP IV inhibitors and how to prepare them.
  • DPP IV inhibitors refers to Vidagliptin, Saxagliptin, and Linagliptin free base and their salts, except when explicitly noted otherwise.
  • 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.
  • 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.
  • amorphous film coating refers to a film comprising API and a pharmaceutical polymer mixture in which API molecules exist in their amorphous form.
  • 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.
  • amorphous API or amorphous API-polymer mixtures may be prepared by freeze- drying or spray-drying methods.
  • 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.
  • the present invention relates to a pharmaceutical composition of amorphous film coated tablets dosage forms according to the invention.
  • a processing method for preparation of amorphous film coated tablets comprises:
  • 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,
  • the present invention relates to processes for preparing the pharmaceutical compositions according to some embodiments of the present invention.
  • the process for preparing the pharmaceutical compositions comprises:
  • step (1) converting the solution or suspension provided in step (1) into a solid particulate form.
  • the process for preparation of pharmaceutical composition according to present invention may comprise the following steps:
  • the process for preparation of pharmaceutical composition may comprise the following steps:
  • DPP-4 inhibitors may be used to prepare amorphous materials without combining with other polymers using the method below:
  • this solvent may be aqueous solution, such as water, water containing solutions.
  • active pharmaceutical ingredients 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.
  • acids may be used as a pH modifier and the pH value is preferably from 1.0 to 7.0.
  • DPP IV inhibitor refers to Vidagliptin, Saxagliptin, and Linagliptin, or their pharmaceutically acceptable salts thereof.
  • 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.
  • compositions may be selected from the group consisting of
  • polyvinypyrrolidone 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.
  • PVA polyvinypyrrolidone
  • HPMC hydroxypropyl methylcellulose
  • Na CMC sodium carboxymethylcellulose
  • hydroxyethyl cellulose and/or cellulose related derivatives
  • xanthan gums pectins
  • alginates Arabic gum and its derivatives
  • starch and its derivatives starch and its derivatives
  • dextrans and its derivatives and other film forming polymers.
  • 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).
  • PVP Polyvinypyrrolidone
  • PVA polyvinyl alcohol
  • HPMC hydroxypropyl methylcellulose
  • HPC hyroxypropyl cellulose
  • Na CMC sodium carboxymethylcellulose
  • 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.
  • 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.
  • 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.
  • the plasticizer may be mono- and di-saccharides, polyethylene glycol and/or its related derivatives, and/or mixtures of the same.
  • 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.
  • the alcohol may be selected from methanol, ethanol, isopropanol and/or mixture thereof.
  • the solvent is water and/or ethanol, and/or a mixture of both.
  • 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
  • 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, .
  • 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.
  • the blank core tablets and pellets may be prepared with a pharmaceutical composition of common
  • 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.
  • 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.
  • the fillers is selected from microcrystalline cellulose and its related materials, lactose, surcrose, mannitol, diabasic calucium phosphate., and/or their mixture thereof.
  • 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.
  • 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.
  • the pharmaceutical disintegrant may be selected from the group consisting of crospovidone, starch and its related derivatives, carboxymethylcellulose sodium,
  • the pharmaceutical composition comprises crospovidone as a disintegrant.
  • 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.
  • the pharmaceutical composition comprises magnesium stearate as lubricant.
  • 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.
  • 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.
  • 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.
  • 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
  • Figure 1 shows the Powder XRD Pattern of Original Vildagliptin Crystal.
  • Figure 2 shows the Powder XRD Pattern of Amorphous Vildagliptin Prepare in Example 1.
  • Figure 3 shows the Powder XRD Pattern of Amorphous Vildagliptin Prepared in Example 2.
  • Figure 4 shows the Powder XRD pattern of Amorphous Vildagliptin prepared from Example 3.
  • Figure 5 shows the Powder XRD Pattern of original Linagliptin crystal.
  • Figure 6 shows the Powder XRD Pattern of the amorphous Linagliptin prepared from Example 4.
  • Figure 7 shows the Dissolution profile of Vildagliptin direct compressed tablets prepared from Example 5.
  • Figure 8 shows the Dissolution profile of amorphous Vildagliptin filmed coated tablet formulation from Example 6.
  • Figure 9 shows the Powder XRD Pattern of the original Saxagliptin free base.
  • Figure 10 shows the Powder XRD Pattern of the amorphous Saxagliptin prepared from Example 7.
  • amorphous API refers to the polymer and API mixture in which API molecules are uniformly distributed without substantial crystal forms.
  • 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.
  • 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.
  • Example 3 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.
  • 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.
  • 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.
  • 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.

Abstract

L'invention concerne des préparations amorphes de composés et compositions pharmaceutiques, et des méthodes associées. L'invention concerne plus particulièrement des préparations amorphes d'inhibiteurs de DPP4 pour le traitement du diabète, et des méthodes de préparation de substances médicamenteuses amorphes et leur conversion sous forme de préparations solides orales.
PCT/US2014/031785 2013-04-29 2014-03-25 Préparations amorphes et méthodes associées WO2014193528A1 (fr)

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Cited By (4)

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CN104856970A (zh) * 2015-06-23 2015-08-26 孙丽华 一种治疗ⅱ型糖尿病的维格列汀片剂
WO2017060398A1 (fr) * 2015-10-09 2017-04-13 Hexal Ag Composition pharmaceutique contenant de la 8-[(3r)-3-amino-1-pipéridinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-méthyl-1-[4-méthyl-2-quinazolinyl)méthyl]-1h-purine-2,6-dione ou son sel pharmaceutiquement acceptable
CN106924207A (zh) * 2015-12-31 2017-07-07 深圳翰宇药业股份有限公司 一种维格列汀片剂及其制备方法
JP2020070260A (ja) * 2018-10-31 2020-05-07 沢井製薬株式会社 テネリグリプチン含有医薬組成物、テネリグリプチン含有医薬組成物の製造方法、テネリグリプチン含有錠剤及びテネリグリプチン含有錠剤の製造方法

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US20130059873A1 (en) * 2002-09-19 2013-03-07 David J. Madar Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)
US20110200672A1 (en) * 2004-05-28 2011-08-18 Bristol-Myers Squibb Company Coated tablet formulation and method
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US20100323011A1 (en) * 2008-03-04 2010-12-23 Nazaneen Pourkavoos Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
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CN104856970A (zh) * 2015-06-23 2015-08-26 孙丽华 一种治疗ⅱ型糖尿病的维格列汀片剂
WO2017060398A1 (fr) * 2015-10-09 2017-04-13 Hexal Ag Composition pharmaceutique contenant de la 8-[(3r)-3-amino-1-pipéridinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-méthyl-1-[4-méthyl-2-quinazolinyl)méthyl]-1h-purine-2,6-dione ou son sel pharmaceutiquement acceptable
US20180243310A1 (en) * 2015-10-09 2018-08-30 Hexal Ag Pharmaceutical composition containing 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof
JP2018530566A (ja) * 2015-10-09 2018-10-18 ヘクサル・アクチェンゲゼルシャフトＨｅｘａｌ ＡＧ ８−［（３ｒ）−３−アミノ−１−ピペリジニル］−７−（２−ブチン−１−イル）−３，７−ジヒドロ−３−メチル−１−［４−メチル−２−キナゾリニル）メチル］−１ｈ−プリン−２，６−ジオンまたは薬学上許容できるその塩を含有する医薬組成物
US10668073B2 (en) 2015-10-09 2020-06-02 Hexal Ag Pharmaceutical composition containing 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof
EA037498B1 (ru) * 2015-10-09 2021-04-05 Хексаль Аг Фармацевтическая композиция, содержащая 8-[(3r)-3-амино-1-пиперидинил]-7-(2-бутин-1-ил)-3,7-дигидро-3-метил-1-[4-метил-2-хиназолинилметил]-1h-пурин-2,6-дион или его фармацевтически приемлемую соль
CN106924207A (zh) * 2015-12-31 2017-07-07 深圳翰宇药业股份有限公司 一种维格列汀片剂及其制备方法
JP2020070260A (ja) * 2018-10-31 2020-05-07 沢井製薬株式会社 テネリグリプチン含有医薬組成物、テネリグリプチン含有医薬組成物の製造方法、テネリグリプチン含有錠剤及びテネリグリプチン含有錠剤の製造方法
JP7117975B2 (ja) 2018-10-31 2022-08-15 沢井製薬株式会社 テネリグリプチン含有医薬組成物、テネリグリプチン含有医薬組成物の製造方法、テネリグリプチン含有錠剤及びテネリグリプチン含有錠剤の製造方法

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