[go: up one dir, main page]

WO2013169523A1 - Solubility enhanced compositions - Google Patents

Solubility enhanced compositions Download PDF

Info

Publication number
WO2013169523A1
WO2013169523A1 PCT/US2013/038825 US2013038825W WO2013169523A1 WO 2013169523 A1 WO2013169523 A1 WO 2013169523A1 US 2013038825 W US2013038825 W US 2013038825W WO 2013169523 A1 WO2013169523 A1 WO 2013169523A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
poorly soluble
solubility
drug
soluble drug
Prior art date
Application number
PCT/US2013/038825
Other languages
French (fr)
Inventor
Sampada Bhaskar UPADHYE
Zahra Nasrin MAHMOUDI
Ali Rajabi-Siahboomi
Thomas P. Farrell
Original Assignee
Bpsi Holdings, Llc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bpsi Holdings, Llc. filed Critical Bpsi Holdings, Llc.
Publication of WO2013169523A1 publication Critical patent/WO2013169523A1/en

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the present invention relates to compositions comprising synergistic combinations of polymeric components and poorly soluble drugs with enhanced solubility of the drugs.
  • the invention also relates to pharmaceutical dosage forms prepared with these compositions.
  • polymers include cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMC-P), polyvinylacetate phthalate (PVAP), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP).
  • CAP cellulose acetate phthalate
  • HPMC hydroxypropylmethyl cellulose
  • HPMC-P hydroxypropylmethylcellulose phthalate
  • PVAP polyvinylacetate phthalate
  • PVA polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • compositions comprising two polymers and a poorly soluble drug with the drug being present predominantly, if not exclusively, in the amorphous state.
  • Some preferred aspects of the invention include compositions containing a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug having a solubility at least 1.5 times greater than the equilibrium solubility of the crystalline form of the drug.
  • PVAP polyvinyl acetate phthalate
  • Such compositions may be prepared by dissolving the polymeric components and the drug in a common solvent system of one or more solvents and then evaporating the solvent to yield a substantially dry powder with drug primarily in the amorphous form.
  • the powder includes the primarily amorphous form of the drug intimately in contact with but not covalently bound to the blend of polymers.
  • a further aspect of the invention includes solvent systems containing the above mentioned poorly soluble drug, cellulosic polymer and PVAP as a dissolved mixture therein.
  • the dissolved mixture of polymers and drug may be coated onto sugar spheres or other pharmaceutically acceptable substrates, which upon evaporation of the solvent system, yields a layer of polymers and substantially amorphous drug on the surface of the sugar spheres.
  • the polymers employed are polyvinylacetate phthalate (PVAP) and hydroxymethylpropyl cellulose (HPMC).
  • pharmaceutical dosage forms such as tablets, capsules or the like that include the solubility-enhanced drugs, prepared as stated above, e.g. as a powder or coated sphere, along with commonly used pharmaceutical excipients to prepare tablets, capsules and other orally-ingestible dosage forms that are known in the art.
  • a method of enhancing the solubility of a poorly soluble amorphous drug includes dissolving a poorly soluble drug in crystalline form in a solvent system along with a mixture of two polymers, preferably the cellulosic polymer and PVAP, followed by evaporating the solvent to yield substantially dry powder containing the amorphous drug intimately in contact with but not covalently bound to the blend of polymers.
  • Fig. 1 is a graph displaying the dissolution profile of the product of Example 1 and Comparative Examples A-E.
  • Fig. 2 is a graph displaying the dissolution profile of the products of Examples 1-4 and Comparative Examples A-E.
  • amorphous shall be understood to mean a substantially random array of molecules in the solid state - i.e. non-crystalline;
  • non-sink shall be understood to mean dissolution conditions under which the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug;
  • orally-ingestible dosage form shall be understood to mean any
  • pharmaceutically acceptable dosage form e.g. tablet, capsule, caplet, etc. or any other veterinary or confectionary product capable of being taken via the oral route of administration;
  • the poorly soluble drugs contemplated for inclusion in the compositions and methods of the invention typically have a measured solubility of ⁇ 0.01 g/mL in water.
  • the inventive solubility-enhanced compositions comprise a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug.
  • the cellulosic polymer may be hydroxypropylmethyl cellulose (HPMC). Low viscosity grades of HPMC are preferred.
  • HPMC having viscosities of less than about 100 centipoise as 2% (w/v) solutions in water are particularly preferred.
  • Suitable commercially available HPMC products include those sold under the Methocel ® trade name with grades such as E3 being well suited for inclusion herein.
  • PVAP is a reaction product of phthalic anhydride and partially hydrolyzed polyvinyl acetate. During the phthalic anhydride addition process, the free hydroxyl groups on the partially hydrolyzed polyvinyl acetate are partially esterified with phthalate groups. Thus, there are acetate, phthalate and free (unreacted) hydroxyl groups on the PVAP polymer backbone.
  • the poorly soluble drug may be any drug having a solubility of ⁇ 0.01 g/mL in water.
  • Poorly soluble drugs possessing functional groups capable of interacting with the functional groups on the cellulosic polymer and PVAP are preferred.
  • Drug molecules possessing sufonylurea, sulfonamide, halogen, alcohol, amine, amide, phenyl, pyrazole, triazole, triazolone, dioxolane, ether, ketone, piperazine or pyrazine groups are particularly preferred.
  • Glipizide, itraconazole, celecoxib and fenofibrate are particularly preferred, since they contain one or more of the functional groups mentioned above.
  • the hydroxyl groups on the cellulosic polymer and PVAP can form hydrogen bonds with electronegative species on drug molecules such as oxygen or nitrogen atoms. Furthermore, the phenyl groups on PVAP can form ⁇ - ⁇ (Pi-Pi) interactions with other aromatic groups on drug molecules to further stabilize the molecular associations.
  • the combination of these stabilizing interactions from both the cellulosic polymer and PVAP leads to a synergistic stabilization of the drug molecule - i.e. the polymers in combination more effectively stabilize the amorphous form of a poorly soluble drug than either polymer alone. It is appreciated that, depending on the nature of the drug molecule, the optimum ratio of cellulosic polymer to PVAP may change.
  • the amount of poorly soluble drug in a composition (i.e. drug concentration) comprising the drug, cellulosic polymer and PVAP may be as high as 50% w/w.
  • a poorly soluble drug concentration less than about 40% is preferred.
  • powder compositions can include up to about 50-99.9%) of the polymer blend.
  • a poorly soluble drug concentration less than about 30%> is particularly preferred.
  • a preferred ratio of cellulosic polymer to PVAP may change depending on the nature of the poorly soluble drug. It is generally preferred that the ratio of cellulosic polymer to PVAP be greater than 1.
  • the ratio of cellulosic polymer to PVAP is at least about 2: 1 while in other aspects, the ratio of cellulosic polymer to PVAP of 3: 1 is more preferred.
  • Surfactants, disintegrants and hydrophilic agents may be incorporated in the compositions comprising poorly soluble drug, cellulosic polymer and PVAP to further enhance the drug solubility and/or dissolution rate.
  • Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates.
  • Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, StarCap 1500®, croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate.
  • Suitable hydrophilic agents used to facilitate water ingress into the compositions, include polyethylene glycols, lactose, mannitol and other water-soluble sugars.
  • a general method for preparing the inventive compositions is to dissolve the poorly soluble drug, cellulosic polymer and PVAP in a common solvent and then evaporate the solvent in a rotary evaporator, or other equipment designed for solvent removal such as a spray dryer, to yield an amorphous solid dispersion.
  • An alternate method for preparing the inventive compositions is to coat the solution of poorly soluble drug, cellulosic polymer and PVAP in a common solvent onto sugar spheres or similar substrate, removing the solvent in the process and yielding a substantially
  • Suitable solvents include dichloromethane, chloroform, methanol, ethanol, acetone, water and mixtures thereof.
  • dichloromethane and methanol can be used successfully as solvents for poorly soluble drugs.
  • the in vitro solubility of the drug within the inventive composition is routinely determined by placing the drug in an aqueous medium within a dissolution vessel with stirring. Samples are then taken at regular time intervals and measured using a spectrophotometer capable of measuring at the wavelength at which the drug molecule absorbs. In this way, the amount of drug dissolved versus time can be determined.
  • it is important to establish non-sink conditions in the dissolution medium i.e. the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug.
  • the amount of drug dissolved from the inventive compositions can then be compared to the amount of crystalline drug dissolved to determine whether any enhancement has been attained.
  • compositions comprising poorly soluble drug, cellulosic polymer and PVAP may be further processed into common orally-ingestible dosage forms.
  • hard gelatin capsules may be filled with the solid dispersions or coated pellets along with excipients such as disintegrants, flow aids and surfactants.
  • compositions may be further formulated with tabletting excipients such as disintegrants, flow aids, binders, surfactants and lubricants and compressed into tablets.
  • tabletting excipients such as disintegrants, flow aids, binders, surfactants and lubricants and compressed into tablets.
  • the tablets may also be coated with film coatings.
  • Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, or StarCap 1500® croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate.
  • Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates.
  • Suitable lubricants include magnesium stearate and stearic acid.
  • Flow aids include colloidal silicon dioxide and talc.
  • the binder may be microcrystalline cellulose (MCC), lactose, calcium phosphate dehydrate (DCP), a fully or partially pre-gelatinized starch such as Starch 1500, or StarCap 1500, trademarks of Colorcon.
  • MCC microcrystalline cellulose
  • DCP calcium phosphate dehydrate
  • Starch 1500 or StarCap 1500, trademarks of Colorcon.
  • the examples below demonstrate that the blend of polymers, when evaporated with the poorly soluble drug, enhances the solubility of the drug better than when either polymer is used alone in a similar system. In many aspects, the enhancement in solubility achieved by the blend is clearly synergistic. While additional amounts of a single polymer may in theory be capable further enhancing the solubility of specific drugs, there are sometimes concerns and drawbacks associated with using excessive amounts of polymer.
  • drugs having lower per milligram potency would not benefit from systems containing more than 80% of a single polymer. Such systems would cause the final dosage form to be unnecessarily bulky, potentially difficult to swallow and thus undesirable in the eyes of the consumer. Stated in another way, the amount of inventive blend needed for a therapeutic dosage would be too great to fit in a suitable oral dosage form.
  • the amount of PVAP is too high relative to the other excipients in the dosage form, an enteric release or an otherwise undesirable pharmacokinetic release profile may be observed.
  • Economic considerations also come into play, which dictate using minimal amounts of polymer to achieve the desired result of enhanced solubility. That is, lower amounts of polymer blends rather than higher amounts of single polymers allow the solubility of the drug to be enhanced thus reducing material costs, spray drying time, etc.
  • Example 1 Solid Dispersion Comprising GZrHPMC E3:PVAP (1:3:1)
  • Solid dispersions were prepared in the same manner as in Example 1 except that the ratios of glipizide :HPMC E3:PVAP were 1 :2:2 and 1 : 1 :3 for Examples 2 and 3, respectively.
  • Glipizide 50 grams
  • PVAP 50 grams
  • HPMC E3 150 grams
  • a methanol-dichloromethane (1 : 1) solvent system to give a total solute concentration of 7% (w/v).
  • 1 Kg of Suglets® sugar spheres 20-25 mesh (850-7 ⁇ ) were loaded into the fluid bed processor (Glatt GPCG 2), equipped with a 4-inch Wurster column, and heated with dry air to a temperature of 35°C.
  • the previously prepared solution of glipizide, PVAP and HPMC E3 was then sprayed onto the fluidized sugar spheres.
  • Solid dispersions were prepared in the same manner as in Example 1 except that only one polymer was used in each case, and the ratio of single polymer to glipizide was 4: 1.
  • HPMC-AS, HPMC E3 and PVAP were used as the single polymer for Comparative Examples A, B and C, respectively.
  • the concentration of non-solvent ingredients in the methanol-dichloromethane solvent was again 6.2% (w/w).
  • Crystalline glipizide was used without further modification.
  • Dissolution was performed using a USP dissolution Apparatus II (Distek dissolution system model 2100, USA) connected to a UV-VIS spectrophotometer (Agilent, USA).
  • the compositions were tested by establishing non-sink dissolution condition as follows. Each solid dispersion (2 g overall; 417 mg glipizide on a theoretical basis) was added to 500 mL of USP phosphate buffer (pH 7.5). In the case of coated sugar spheres, 12 grams were added to the dissolution vessel, which again was equivalent to 417 mg glipizide on a theoretical basis.
  • the theoretical concentration of glipizide in the dissolution medium was 0.834 mg/mL, which is three times the equilibrium solubility of crystalline glipizide.
  • the dissolution medium was maintained at 37 ⁇ 0.5 °C, and the paddle speed was 50 rpm. Samples were
  • Example 5 Solid Dispersion Comprising ITZrHPMC E3:PVAP (1:3:1)
  • Example 6 Solid Dispersion Comprising Celecoxib: HPMC E3:PVAP (1:3:1)

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Solubility-enhanced compositions comprising synergistic combinations of cellulosic polymers, polyvinyl acetate phthalate and poorly soluble drugs are provided. The poorly soluble drugs in the solubility-enhanced compositions have apparent aqueous solubilities at least 1.5 times higher than the equilibrium solubilities of the crystalline forms of the drugs. Orally-ingestible dosage forms comprising these solubility-enhanced compositions are also disclosed.

Description

SOLUBILITY ENHANCED COMPOSITIONS
Cross Reference to Related Applications
This Application claims the benefit of priority from US Provisional Patent Application Serial Number 61/643,579, filed May 7, 2012, the contents of which are incorporated herein by reference.
1. Field of the Invention
The present invention relates to compositions comprising synergistic combinations of polymeric components and poorly soluble drugs with enhanced solubility of the drugs. The invention also relates to pharmaceutical dosage forms prepared with these compositions.
2. Description of the Prior Art
The use of polymeric components to enhance the solubility of drugs by increasing their dissolution rates, extent of supersaturation and maintenance of supersaturation has been well-established in the prior art. One of the primary ways this is achieved is by preparing an amorphous form of the drug by dissolving or melting the drug in the presence of a polymeric component. Upon solvent removal or solidification of the drug in the presence of a polymeric component, a stabilized amorphous form of the drug can be prepared. Thus, binary combinations of various polymers and poorly soluble drugs are known. Hydroxypropylmethylcellulose acetate succinate (HPMC- AS) is a preferred polymer used for this purpose in the prior art (W. Curatolo, J.A. Nightingale and S. Herbig, Pharmaceutical Research, Vol. 26, No. 6, June 2009). In this same work, other polymers were reported to enhance drug solubility but to a lesser extent than HPMC-AS. These polymers include cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMC-P), polyvinylacetate phthalate (PVAP), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). 3. Summary of the Invention
It has been surprisingly found that the use of two polymers enhances the solubility of a poorly soluble drug to a greater extent than either polymer alone.
In one aspect of the invention, there are compositions comprising two polymers and a poorly soluble drug with the drug being present predominantly, if not exclusively, in the amorphous state. Some preferred aspects of the invention include compositions containing a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug having a solubility at least 1.5 times greater than the equilibrium solubility of the crystalline form of the drug. Such compositions may be prepared by dissolving the polymeric components and the drug in a common solvent system of one or more solvents and then evaporating the solvent to yield a substantially dry powder with drug primarily in the amorphous form. The powder includes the primarily amorphous form of the drug intimately in contact with but not covalently bound to the blend of polymers.
A further aspect of the invention includes solvent systems containing the above mentioned poorly soluble drug, cellulosic polymer and PVAP as a dissolved mixture therein. The dissolved mixture of polymers and drug may be coated onto sugar spheres or other pharmaceutically acceptable substrates, which upon evaporation of the solvent system, yields a layer of polymers and substantially amorphous drug on the surface of the sugar spheres. In preferred aspects of this invention, the polymers employed are polyvinylacetate phthalate (PVAP) and hydroxymethylpropyl cellulose (HPMC).
In another aspect of the invention, there are provided pharmaceutical dosage forms such as tablets, capsules or the like that include the solubility-enhanced drugs, prepared as stated above, e.g. as a powder or coated sphere, along with commonly used pharmaceutical excipients to prepare tablets, capsules and other orally-ingestible dosage forms that are known in the art.
In yet a further aspect of the invention there is provided a method of enhancing the solubility of a poorly soluble amorphous drug. The method includes dissolving a poorly soluble drug in crystalline form in a solvent system along with a mixture of two polymers, preferably the cellulosic polymer and PVAP, followed by evaporating the solvent to yield substantially dry powder containing the amorphous drug intimately in contact with but not covalently bound to the blend of polymers.
The solubility enhancement of a poorly soluble drug using the polymer blends described herein is clearly superior over the prior art using solvent systems containing just one polymer. 4. Brief Description of the Drawings
Fig. 1 is a graph displaying the dissolution profile of the product of Example 1 and Comparative Examples A-E.
Fig. 2 is a graph displaying the dissolution profile of the products of Examples 1-4 and Comparative Examples A-E.
5. Detailed Description of the Invention
For purposes of the present invention, the following terms are given further clarification as to their meanings:
"amorphous" shall be understood to mean a substantially random array of molecules in the solid state - i.e. non-crystalline;
"non-sink" shall be understood to mean dissolution conditions under which the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug; "orally-ingestible dosage form" shall be understood to mean any
pharmaceutically acceptable dosage form, e.g. tablet, capsule, caplet, etc. or any other veterinary or confectionary product capable of being taken via the oral route of administration;
"poorly soluble drug" shall be understood to mean any drug that has very limited solubility in aqueous media or biological fluids found in the gastrointestinal tract. The poorly soluble drugs contemplated for inclusion in the compositions and methods of the invention typically have a measured solubility of < 0.01 g/mL in water. The inventive solubility-enhanced compositions comprise a cellulosic polymer, polyvinyl acetate phthalate (PVAP) and a poorly soluble drug. The cellulosic polymer may be hydroxypropylmethyl cellulose (HPMC). Low viscosity grades of HPMC are preferred. Grades of HPMC having viscosities of less than about 100 centipoise as 2% (w/v) solutions in water are particularly preferred. Suitable commercially available HPMC products include those sold under the Methocel® trade name with grades such as E3 being well suited for inclusion herein.
PVAP is a reaction product of phthalic anhydride and partially hydrolyzed polyvinyl acetate. During the phthalic anhydride addition process, the free hydroxyl groups on the partially hydrolyzed polyvinyl acetate are partially esterified with phthalate groups. Thus, there are acetate, phthalate and free (unreacted) hydroxyl groups on the PVAP polymer backbone.
The poorly soluble drug may be any drug having a solubility of < 0.01 g/mL in water. Poorly soluble drugs possessing functional groups capable of interacting with the functional groups on the cellulosic polymer and PVAP are preferred. Drug molecules possessing sufonylurea, sulfonamide, halogen, alcohol, amine, amide, phenyl, pyrazole, triazole, triazolone, dioxolane, ether, ketone, piperazine or pyrazine groups are particularly preferred. Glipizide, itraconazole, celecoxib and fenofibrate are particularly preferred, since they contain one or more of the functional groups mentioned above.
While not wishing to be bound by any particular theory, it is believed that when the cellulosic polymer, PVAP and poorly soluble drug are dissolved in a common solvent and the solvent is then evaporated, the drug transforms from a crystalline to an amorphous state, which is stabilized by hydrophilic and hydrophobic interactions with the cellulosic polymer and PVAP. Since an amorphous form of a drug is inherently more soluble than a crystalline form, the solubility of the poorly soluble drug in the polymeric composition is enhanced, and the solubility-enhanced form is stabilized from recrystallization both as a solid dispersion and when dissolved in an aqueous medium. The hydroxyl groups on the cellulosic polymer and PVAP can form hydrogen bonds with electronegative species on drug molecules such as oxygen or nitrogen atoms. Furthermore, the phenyl groups on PVAP can form π-π (Pi-Pi) interactions with other aromatic groups on drug molecules to further stabilize the molecular associations. The combination of these stabilizing interactions from both the cellulosic polymer and PVAP leads to a synergistic stabilization of the drug molecule - i.e. the polymers in combination more effectively stabilize the amorphous form of a poorly soluble drug than either polymer alone. It is appreciated that, depending on the nature of the drug molecule, the optimum ratio of cellulosic polymer to PVAP may change.
The amount of poorly soluble drug in a composition (i.e. drug concentration) comprising the drug, cellulosic polymer and PVAP may be as high as 50% w/w. A poorly soluble drug concentration less than about 40% is preferred. Thus, powder compositions can include up to about 50-99.9%) of the polymer blend. A poorly soluble drug concentration less than about 30%> is particularly preferred. A preferred ratio of cellulosic polymer to PVAP may change depending on the nature of the poorly soluble drug. It is generally preferred that the ratio of cellulosic polymer to PVAP be greater than 1. In some aspects, the ratio of cellulosic polymer to PVAP is at least about 2: 1 while in other aspects, the ratio of cellulosic polymer to PVAP of 3: 1 is more preferred. Surfactants, disintegrants and hydrophilic agents may be incorporated in the compositions comprising poorly soluble drug, cellulosic polymer and PVAP to further enhance the drug solubility and/or dissolution rate. Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates. Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, StarCap 1500®, croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate. Suitable hydrophilic agents, used to facilitate water ingress into the compositions, include polyethylene glycols, lactose, mannitol and other water-soluble sugars. A general method for preparing the inventive compositions is to dissolve the poorly soluble drug, cellulosic polymer and PVAP in a common solvent and then evaporate the solvent in a rotary evaporator, or other equipment designed for solvent removal such as a spray dryer, to yield an amorphous solid dispersion. An alternate method for preparing the inventive compositions is to coat the solution of poorly soluble drug, cellulosic polymer and PVAP in a common solvent onto sugar spheres or similar substrate, removing the solvent in the process and yielding a substantially
homogenous mixture of poorly soluble drug, cellulosic polymer and PVAP as a coating on the sugar spheres. Suitable solvents include dichloromethane, chloroform, methanol, ethanol, acetone, water and mixtures thereof. For example, mixtures of dichloromethane and methanol can be used successfully as solvents for poorly soluble drugs.
The in vitro solubility of the drug within the inventive composition is routinely determined by placing the drug in an aqueous medium within a dissolution vessel with stirring. Samples are then taken at regular time intervals and measured using a spectrophotometer capable of measuring at the wavelength at which the drug molecule absorbs. In this way, the amount of drug dissolved versus time can be determined. In order to determine whether solubility has been enhanced, it is important to establish non-sink conditions in the dissolution medium - i.e. the concentration of a drug, in dissolved and/or undissolved form, is greater than the equilibrium solubility of the crystalline drug. The amount of drug dissolved from the inventive compositions can then be compared to the amount of crystalline drug dissolved to determine whether any enhancement has been attained. One can readily compare the relative solubilities of the inventive compositions and the crystalline forms and express the solubility of the drug within the inventive compositions as a multiple of the equilibrium solubility of the crystalline form of the drug. It is desirable to enhance the solubility of a poorly soluble drug within an inventive composition such that the concentration of the drug in an aqueous medium is at least 1.5 times that of the equilibrium solubility of the crystalline form of the drug. Depending upon the drug selected for inclusion, the increase in solubility can be many times higher. See Examples below.
The inventive compositions comprising poorly soluble drug, cellulosic polymer and PVAP may be further processed into common orally-ingestible dosage forms. For example, hard gelatin capsules may be filled with the solid dispersions or coated pellets along with excipients such as disintegrants, flow aids and surfactants.
Alternatively, the same compositions may be further formulated with tabletting excipients such as disintegrants, flow aids, binders, surfactants and lubricants and compressed into tablets. The tablets may also be coated with film coatings. Suitable disintegrants include native starch or partially pre-gelatinized starch such as Starch 1500®, or StarCap 1500® croscarmellose sodium, sodium stearyl fumarate, crospovidone and sodium starch glycolate. Suitable surfactants include sodium lauryl sulfate, poloxamers and polysorbates. Suitable lubricants include magnesium stearate and stearic acid. Flow aids include colloidal silicon dioxide and talc. The binder may be microcrystalline cellulose (MCC), lactose, calcium phosphate dehydrate (DCP), a fully or partially pre-gelatinized starch such as Starch 1500, or StarCap 1500, trademarks of Colorcon. The examples below demonstrate that the blend of polymers, when evaporated with the poorly soluble drug, enhances the solubility of the drug better than when either polymer is used alone in a similar system. In many aspects, the enhancement in solubility achieved by the blend is clearly synergistic. While additional amounts of a single polymer may in theory be capable further enhancing the solubility of specific drugs, there are sometimes concerns and drawbacks associated with using excessive amounts of polymer. For example, drugs having lower per milligram potency would not benefit from systems containing more than 80% of a single polymer. Such systems would cause the final dosage form to be unnecessarily bulky, potentially difficult to swallow and thus undesirable in the eyes of the consumer. Stated in another way, the amount of inventive blend needed for a therapeutic dosage would be too great to fit in a suitable oral dosage form. In addition, if the amount of PVAP is too high relative to the other excipients in the dosage form, an enteric release or an otherwise undesirable pharmacokinetic release profile may be observed. Economic considerations also come into play, which dictate using minimal amounts of polymer to achieve the desired result of enhanced solubility. That is, lower amounts of polymer blends rather than higher amounts of single polymers allow the solubility of the drug to be enhanced thus reducing material costs, spray drying time, etc.
EXAMPLES
Example 1 - Solid Dispersion Comprising GZrHPMC E3:PVAP (1:3:1)
1 part crystalline glipizide (GZ), 1 part PVAP and 3 parts HPMC E3 (viscosity of 3 centipoise in a 2% aqueous solution) were dissolved in a mixture of 28.5 parts methanol and 47.7 parts dichloromethane (1 : 1 volume ratio) to yield a solution containing 6.2% of solutes (w/w). The solvents were evaporated over a 30-minute period using a Biichi rotary evaporator (Biichi RotaVapor, RII, Biichi USA) under vacuum until a visibly dry material was obtained. The solid dispersion was further dried in a vacuum oven at 40°C for 12 hours to remove residual solvent. The dried dispersions were subsequently milled using a Waring grinder at 19,000 rpm and passed through a 40 mesh (425 micron) sieve.
Examples 2-3
Solid dispersions were prepared in the same manner as in Example 1 except that the ratios of glipizide :HPMC E3:PVAP were 1 :2:2 and 1 : 1 :3 for Examples 2 and 3, respectively.
Example 4 - Sugar Spheres Coated with GZrHPMC E3:PVAP (1:3:1)
Glipizide (50 grams), PVAP (50 grams) and HPMC E3 (150 grams) were dissolved in 3.6 L of a methanol-dichloromethane (1 : 1) solvent system to give a total solute concentration of 7% (w/v). 1 Kg of Suglets® sugar spheres 20-25 mesh (850-7 ΙΟμιη) were loaded into the fluid bed processor (Glatt GPCG 2), equipped with a 4-inch Wurster column, and heated with dry air to a temperature of 35°C. The previously prepared solution of glipizide, PVAP and HPMC E3 was then sprayed onto the fluidized sugar spheres. The bed temperature was maintained at 32-35°C while the solution was sprayed at a spray rate of 15-20g/min and an atomizing air pressure of about 1 bar. Once the solution had been completely sprayed, the coated spheres were removed from the coating pan and weighed. 1.2075 Kg of coated spheres were thus obtained, which corresponds to an overall yield of 97%. Assuming no attrition of the sugar spheres, the coating efficiency of the solutes was 83% (207.5 grams coating/250 grams solute x 100). Comparative Examples A-C
Solid dispersions were prepared in the same manner as in Example 1 except that only one polymer was used in each case, and the ratio of single polymer to glipizide was 4: 1. HPMC-AS, HPMC E3 and PVAP were used as the single polymer for Comparative Examples A, B and C, respectively. The concentration of non-solvent ingredients in the methanol-dichloromethane solvent was again 6.2% (w/w).
Comparative Example D
Crystalline glipizide was used without further modification.
Comparative Example E
1 part crystalline glipizide, 1 part PVAP and 3 parts HPMC E3 were mixed in the solid state and passed through a 40 # screen for uniform mixing. A simple physical mixture of the three components was thus obtained.
Dissolution Testing
Dissolution was performed using a USP dissolution Apparatus II (Distek dissolution system model 2100, USA) connected to a UV-VIS spectrophotometer (Agilent, USA). The compositions were tested by establishing non-sink dissolution condition as follows. Each solid dispersion (2 g overall; 417 mg glipizide on a theoretical basis) was added to 500 mL of USP phosphate buffer (pH 7.5). In the case of coated sugar spheres, 12 grams were added to the dissolution vessel, which again was equivalent to 417 mg glipizide on a theoretical basis. In all cases, the theoretical concentration of glipizide in the dissolution medium was 0.834 mg/mL, which is three times the equilibrium solubility of crystalline glipizide. The dissolution medium was maintained at 37±0.5 °C, and the paddle speed was 50 rpm. Samples were
automatically drawn from each vessel through a 0.45 μιη tip filter at specified time intervals and returned to the vessel after passing through a flow cell (1 mm). Quantification of the amount of glipizide released was accomplished by UV detection at 276 nm and averaged (n=3). See Figures 1 and 2 and Table 1 below.
Table 1: Dissolution Data - Inventive Compositions and Comparative Examples
Figure imgf000012_0001
Sapp = apparent solubility of glipizide in the polymeric composition
Scrystai = equilibrium solubility of crystalline glipizide
It can be seen from the data that the blend of polymers in which the cellulosic polyi exceeds the amount of PVAP had superior results. Example 5 - Solid Dispersion Comprising ITZrHPMC E3:PVAP (1:3:1)
1 part crystalline itraconazole (ITZ), 1 part PVAP and 3 parts HPMC E3 (viscosity of 3 centipoise in a 2% aqueous solution) were dissolved in a mixture of 28.5 parts methanol and 47.7 parts dichloromethane (1 : 1 volume ratio) to yield a solution containing 6.2% of solutes (w/w). The solvents were evaporated over a 30-minute period using a Buchi rotary evaporator (Buchi RotaVapor, RII, Buchi USA) under vacuum until a visibly dry material was obtained. The solid dispersion was further dried in a vacuum oven at 40°C for 12 hours to remove residual solvent. The dried dispersions were subsequently milled using a Waring grinder at 19,000 rpm and passed through a 40 mesh (425 micron) sieve. Dissolution testing was conducted in a 0.1 N HC1 medium. The solubility of itraconazole in the inventive solid dispersion was determined to be 83 μg/mL, which is 21 times the equilibrium solubility of crystalline itraconazole in the same medium. Example 6 - Solid Dispersion Comprising Celecoxib: HPMC E3:PVAP (1:3:1)
1 part crystalline celecoxib, 1 part PVAP and 3 parts HPMC E3 (viscosity of 3 centipoise in a 2% aqueous solution) were dissolved in a mixture of 28.5 parts methanol and 47.7 parts dichloromethane (1 : 1 volume ratio) to yield a solution containing 6.2% of solutes (w/w). The solvents were evaporated over a 30-minute period using a Buchi rotary evaporator (Buchi RotaVapor, RII, Buchi USA) under vacuum until a visibly dry material was obtained. The solid dispersion was further dried in a vacuum oven at 40°C for 12 hours to remove residual solvent. The dried dispersions were subsequently milled using a Waring grinder at 19,000 rpm and passed through a 40 mesh (425 micron) sieve. Dissolution testing was conducted in a pH 6.8 phosphate buffer medium. The solubility of celecoxib in the inventive solid dispersion was determined to be 25 μg/mL, which is 5 times the equilibrium solubility of crystalline celecoxib in the same medium. Example 7 - Solid Dispersion Comprising FenofibraterHPMC E3:PVAP (1:3:1)
1 part fenofibrate, 3 parts HPMC E3 and 1 part PVAP were dissolved in 195 parts of a mixture of dichloromethane and methanol (3 : 1 ratio). This resulted in a solution comprising 2.5% (w/w) solutes in solvent. This solution was spray dried using a Buchi B-290 spray dryer to yield a powder, which was subsequently dried for an additional 12 hours at 40°C to remove residual solvent. Dissolution testing of the resulting powder was conducted in a pH 6.5 fasted state simulated intestinal fluid (FaSSIF) medium. The solubility of fenofibrate in the inventive solid dispersion was determined to be 146 μg/mL, which is 292 times the equilibrium solubility of crystalline fenofibrate in the same medium.
Comparative Example F - Solid Dispersion Comprising Fenofibrate:PVAP (1:4)
1 part fenofibrate and 4 parts PVAP were dissolved in 195 parts of a mixture of dichloromethane and methanol (3 : 1 ratio). This resulted in a solution comprising 2.5% (w/w) solutes in solvent. This solution was spray dried using a Buchi B-290 spray dryer to yield a powder, which was subsequently dried for an additional 12 hours at 40°C to remove residual solvent. Dissolution testing of the resulting powder was conducted in a pH 6.5 fasted state simulated intestinal fluid (FaSSIF) medium. The solubility of fenofibrate in the inventive solid dispersion was determined to be 91 μg/mL, which is about 182 times the equilibrium solubility of crystalline fenofibrate in the same medium.
Comparative Example G - Solid Dispersion Comprising Fenofibrate:HPMC E3 (1:4)
1 part fenofibrate and 4 parts HPMC E3 were dissolved in 195 parts of a mixture of dichloromethane and methanol (3 : 1 ratio). This resulted in a solution comprising 2.5% (w/w) solutes in solvent. This solution was spray dried using a Buchi B-290 spray dryer to yield a powder, which was subsequently dried for an additional 12 hours at 40°C to remove residual solvent. Dissolution testing of the resulting powder was conducted in a pH 6.5 fasted state simulated intestinal fluid (FaSSIF) medium. The solubility of fenofibrate in the inventive solid dispersion was determined to be 76 μg/mL, which is about 152 times the equilibrium solubility of crystalline fenofibrate in the same medium.
Comparing the results of Example 7 and Comparative Examples F and G, the synergistic performance of the HPMC E3 / PVAP combination versus either PVAP or HPMC E3 alone can be readily seen:
Figure imgf000015_0001
* Measured concentration after 10 minutes in the dissolution medium.

Claims

WHAT IS CLAIMED:
1. A composition comprising a cellulosic polymer, polyvinyl acetate phthalate and a poorly soluble drug having a solubility at least 1.5 times greater than the equilibrium solubility of the crystalline form of the drug.
2. A composition of claim 1, in substantially dry powder form containing the poorly soluble drug in amorphous form intimately in contact with but not covalently bound to a blend of the cellulosic polymer and the polyvinyl acetate phthalate.
3. The composition of claim 1, wherein said poorly soluble drug has a solubility of less than 0.01 gram/mL in crystalline form.
4. The composition of claim 1, wherein said poorly soluble drug comprises up to 50% by weight of the composition.
5. The composition of claim 1, wherein said poorly soluble drug comprises up to 40% by weight of the composition.
6. The composition of claim 1, wherein said poorly soluble drug comprises up to 30%) by weight of the composition.
7. The composition of claim 1, wherein said cellulosic polymer is a hydroxypropyl- methyl cellulose (HPMC).
8. The composition of claim 7, wherein the HPMC is HPMC E3.
9. The composition of claim 1, wherein the ratio of cellulosic polymer to polyvinyl acetate phthalate is greater than about 1 : 1.
10. The composition of claim 1, wherein the ratio of cellulosic polymer to polyvinyl acetate phthalate is at least about 2: 1.
11. The composition of claim 10, wherein the ratio of cellulosic polymer to polyvinyl acetate phthalate is at least 3 : 1 or greater.
12. The composition of claim 1, further comprising one or more of a surfactant,
disintegrant or hydrophilic agent.
13. The composition of claim 1, wherein the poorly soluble drug includes a moiety selected from the group consisting of sufonylurea, sulfonamide, halogen, alcohol, amine, amide, phenyl, pyrazole, triazole, triazolone, dioxolane, ether, ketone, piperazine and pyrazine groups.
14. The composition of claim 11, wherein the poorly soluble drug is glipizide,
itraconazole, celecoxib or fenofibrate.
15. A composition of claim 1 prepared by dissolving the cellulosic polymer, polyvinyl acetate phthalate and poorly soluble drug in a common solvent system and thereafter drying the resultant mixture to provide the drug in substantially amorphous form.
16. A pharmaceutical composition prepared by dissolving a cellulosic polymer,
polyvinyl acetate phthalate and a poorly soluble drug in a common solvent system and then spray coating the resultant mixture onto sugar spheres or
pharmaceutically acceptable substrates such that the drug is provided in substantially amorphous form on said sugar spheres or substrates upon drying.
17. An orally-ingestible dosage form comprising the solubility-enhanced composition of claim 1.
18. A capsule or tablet containing the solubility-enhanced composition of claim 1 and, optionally, one or more of a disintegrant, surfactant, flow aid, lubricant or binder.
19. A method of enhancing the solubility of a poorly soluble drug, comprising
dissolving a crystalline form of a poorly soluble drug in combination with at least two polymers, evaporating the solvents and recovering a polymeric complex with the poorly soluble drug in substantially amorphous form - the drugs within the polymeric complex having a solubility at least 1.5 times the equilibrium solubility of the crystalline form of the drug.
20. The method of claim 19, wherein the at least two polymers include a cellulosic polymer and polyvinyl acetate phthalate.
PCT/US2013/038825 2012-05-07 2013-04-30 Solubility enhanced compositions WO2013169523A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261643579P 2012-05-07 2012-05-07
US61/643,579 2012-05-07

Publications (1)

Publication Number Publication Date
WO2013169523A1 true WO2013169523A1 (en) 2013-11-14

Family

ID=49551161

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/038825 WO2013169523A1 (en) 2012-05-07 2013-04-30 Solubility enhanced compositions

Country Status (1)

Country Link
WO (1) WO2013169523A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105399692A (en) * 2015-12-18 2016-03-16 四川大学 Glipizide crystal form III, and preparation method thereof
CN112535665A (en) * 2020-12-14 2021-03-23 宁夏医科大学 Glipizide solid dispersion, preparation method thereof, glipizide solid dispersion tablet containing glipizide solid dispersion and preparation method thereof
US12133911B2 (en) 2015-06-09 2024-11-05 Capsugel Belgium Nv Formulations to achieve rapid dissolution of drug from spray-dried dispersions in capsules

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219489A1 (en) * 1997-08-11 2003-11-27 Pfizer Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US20070048377A1 (en) * 2005-08-26 2007-03-01 Ali Rajabi-Siahboomi Drug compositions containing controlled release hypromellose matrices
US7235260B2 (en) * 2000-03-16 2007-06-26 Pfizer Inc Pharmaceutical compositions of a sparingly soluble glycogen phosphorylase inhibitor
US7607596B1 (en) * 2007-03-07 2009-10-27 Exxpharma, LLC Process for enhancing the solubility of poorly soluble drugs
US20100256110A1 (en) * 1999-02-10 2010-10-07 Babcock Walter C Pharmaceutical solid dispersions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219489A1 (en) * 1997-08-11 2003-11-27 Pfizer Inc. Solid pharmaceutical dispersions with enhanced bioavailability
US20100256110A1 (en) * 1999-02-10 2010-10-07 Babcock Walter C Pharmaceutical solid dispersions
US7235260B2 (en) * 2000-03-16 2007-06-26 Pfizer Inc Pharmaceutical compositions of a sparingly soluble glycogen phosphorylase inhibitor
US20070048377A1 (en) * 2005-08-26 2007-03-01 Ali Rajabi-Siahboomi Drug compositions containing controlled release hypromellose matrices
US7607596B1 (en) * 2007-03-07 2009-10-27 Exxpharma, LLC Process for enhancing the solubility of poorly soluble drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE DOW CHEMICAL COMPANY.: "Methocel Cellulose Ethers in Aqueous Systems for Tablet Coating", July 2002 (2002-07-01), Retrieved from the Internet <URL:http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_004a/0901b8038004ab56.pdf?filepath=/198-00755.pdf&fromPage=GetDoc> [retrieved on 20130911] *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12133911B2 (en) 2015-06-09 2024-11-05 Capsugel Belgium Nv Formulations to achieve rapid dissolution of drug from spray-dried dispersions in capsules
CN105399692A (en) * 2015-12-18 2016-03-16 四川大学 Glipizide crystal form III, and preparation method thereof
CN112535665A (en) * 2020-12-14 2021-03-23 宁夏医科大学 Glipizide solid dispersion, preparation method thereof, glipizide solid dispersion tablet containing glipizide solid dispersion and preparation method thereof

Similar Documents

Publication Publication Date Title
JP6505705B2 (en) Method for producing a preparation for oral administration
US9511026B2 (en) Poorly soluble drug containing microspheres with improved bioavailability and method of preparing the same
CN104936589A (en) Pharmaceutical composition with improved bioavailability
KR20090080143A (en) Sustained release dosage forms of ziprasidone
EP1039909A1 (en) Method and composition of an oral preparation of itraconazole
JP2002523443A (en) Omeprazole preparation
RU2372893C2 (en) Coated compound containing pharmaceutical agent
JP2012512840A (en) Solid composition containing rasagiline component
WO2013034040A1 (en) Celecoxib solid dispersion and preparation method therefor
WO2017108605A1 (en) Pharmaceutical composition comprising amorphous dasatinib
EP1104291A1 (en) Pellets having a core coated with an antifungal and a polymer
US20090324728A1 (en) Pharmaceutical compositions comprising amorphous benzimidazole compounds
WO2017032908A1 (en) Pharmaceutical composition comprising amorphous posaconazole
EP3107530A1 (en) Pharmaceutical composition comprising apixaban
WO2017203229A1 (en) Dapagliflozin premixes
TW202227067A (en) Amorphous form of a malt1 inhibitor and formulations thereof
CA2253769C (en) Pharmaceutical compositions comprising fenofibrate
US10660963B2 (en) Pharmaceutical composition containing tacrolimus and preparation methods thereof
EP3793530A1 (en) Solid dispersion containing ritonavir
AU2023269191A1 (en) Glp1 tablet compositions
CN102858325A (en) Oral pharmaceutical composition comprising fenofibric acid and an alkalifying agent
WO2013169523A1 (en) Solubility enhanced compositions
EP2665466A1 (en) Solid molecular dispersion
JP2018024628A (en) Amorphous solid dispersion containing tolvaptan and method for producing the same
MX2007009916A (en) Composition comprising ocaperidone.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13787287

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13787287

Country of ref document: EP

Kind code of ref document: A1