EP2485716A2 - Composition pharmaceutique comprenant un principe actif peu soluble et un polymère hyper-ramifié - Google Patents

Composition pharmaceutique comprenant un principe actif peu soluble et un polymère hyper-ramifié

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Publication number
EP2485716A2
EP2485716A2 EP10771053A EP10771053A EP2485716A2 EP 2485716 A2 EP2485716 A2 EP 2485716A2 EP 10771053 A EP10771053 A EP 10771053A EP 10771053 A EP10771053 A EP 10771053A EP 2485716 A2 EP2485716 A2 EP 2485716A2
Authority
EP
European Patent Office
Prior art keywords
hyperbranched polymer
pharmaceutical composition
hyperbranched
ingredient
carrier
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10771053A
Other languages
German (de)
English (en)
Inventor
Sebastjan Reven
Ema Zagar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
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
Priority claimed from EP09172391A external-priority patent/EP2311435A1/fr
Application filed by Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Priority to EP10771053A priority Critical patent/EP2485716A2/fr
Publication of EP2485716A2 publication Critical patent/EP2485716A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • composition comprising poorly soluble active ingredient and
  • the present invention belongs to the field of pharmaceutical industry and relates to a pharmaceutical composition comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient exhibiting poor solubility in aqueous solvents, wherein the hyperbranched polymer and the pharmaceutically active ingredient (API) are present in a specific weight ratio, and to a process for the preparation of said pharmaceutical composition.
  • the present invention is also directed to a powder or granulate comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient exhibiting poor solubility in aqueous solvents, wherein the polymer and the API are present in a specific weight ratio, to a process for the preparation of said powder or granulate, and to a pharmaceutical dosage form comprising the composition, powder or granulate.
  • the present invention further relates to a process for preparing solid dispersion of a hyperbranched polymer and at least one API, as well as to the use of a crystalline carrier for the preparation of a mixture of a hyperbranched polymer and a pharmaceutically active ingredient.
  • the present invention is also directed to the use of polyesteramide hyperbranched polymers for the preparation of a pharmaceutical composition, to the use of a hydrophilic carrier for the preparation of said composition comprising a specific group of API , and to the use of a specific API and at least one hyperbranched polymer for the preparation of a pharmaceutical composition.
  • Pharmaceutically active ingredients are normally not administered to patients for prophylaxis or treatment just alone, but instead the pharmaceutically active ingredients are usually formulated in pharmaceutical compositions such as powders or tablets, such as coated or uncoated mono- or multilayered tablets.
  • pharmaceutical compositions can be specifically designed to provide the desired dissolution profile.
  • the pharmaceutically active ingredient exhibits the desired pharmacological activity it must reach a sufficient concentration at the site of action. This means that the pharmaceutically active ingredient has to exhibit a certain minimum solubility, which in turn often requires improving the solubility of the respective pharmaceutically active ingredient.
  • solubilization techniques such as the addition of cosolvent, micellar solubilization through surfactants, the use of cyclodextrine, pH modification, solvent recrystallization, spray drying and the like are available in order to solubiilze insoluble or poorly soluble drugs in aqueous or other desired solvents.
  • compositions comprising at least one active substance which is sparingly soluble in water and at least one hyperbranched polymer comprising nitrogen atom.
  • compositions comprising pharmaceutically active ingredients, in particular with regard to the solubility of the pharmaceutically active ingredient, and for an improved process for preparing such a pharmaceutical composition.
  • the present invention provides the following aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, contribute to solving the object of the present invention:
  • a pharmaceutical composition comprising:
  • the weight ratio of the at least one hyperbranched polymer to the at least one active pharmaceutical ingredient is 99: 1 w/w to 1 1 :1 w/w or wherein the weight ratio can even be 99 : 1 w/w to 4 : 1 w/w if the active pharmaceutical ingredient is selected from the group consisting of phosphodiesterase inhibitors, preferably phosphodiesterase II I inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives; or wherein the weight ratio 99:1 w/w to 4:1 w/w if a hyperbranched polyesteramide, preferably a hyperbranched polyesteramide having tertiary amine end groups or having hydroxyl end groups is used as the hyperbranched polymer.
  • the hyperbranched polymer and the pharmaceutically active ingredient form a solid dispersion.
  • a preferred phosphodiesterase III inhibitor is pimobendan, a preferred phosphodiesterase V inhibitor is tadalfil; a preferred non-thiazide sulphonamide is indapamide; a preferred sulfonylurea derivative is glimepiride; and a preferred hydroxy-1 ,4-naphthoquinone derivative is atovaquone.
  • a hyperbranched polyesteramide having tertiary amine end groups is used in order to provide the best solubility of the API.
  • a hyperbranched polyesteramide having hydroxyl end groups is used to provide the lowest hygroscopicity of the pharmaceutical composition, powder or granulate.
  • the weight ratio of hyperbranched polymer/active pharmaceutical according to the invention is 99:1 to 1 1 :1 .
  • the weight ratio is 99:1 to 14:1 , further preferred, the weight ratio is 99:1 to 17:1 , even further preferred, the weight ratio is 99:1 to 18:1 .
  • the weight ratio is 80:1 to 1 1 :1 , further preferred, the weight ratio is 55:1 to 1 1 :1 , even further preferred, the weight ratio is 24:1 to 1 1 :1 .
  • the weight ratio is 80:1 to 14:1 , further preferred, the weight ratio is 55:1 to 17:1 , even further preferred, the weight ratio is 24: 1 to 18: 1 .
  • the weight ratio of hyperbranched polymer and said active pharmaceutical ingredient is 80:20 w/w to 98:2 w/w, preferably 88:12 w/w to 98:2 w/w, more preferably 90:10 w/w to 98:2 w/w, yet more preferably 93:7 w/w to 98:2 w/w, particularly 98:2 w/w to 95:5 w/w, further preferably 98:2 w/w to 95:2 w/w.
  • the hyperbranched polymer and the at least one active pharmaceutical ingredient form a solid dispersion or a solid solution.
  • a solid dispersion is formed between the hyperbranched polymer and the at least one pharmaceutically active ingredient.
  • the solid dispersion or solid solution is obtained by using known techniques (such as high shear mixing, spray drying or fluid bed granulation).
  • a solid dispersion denotes a dispersion of one or more compound(s) in an inert carrier at solid state.
  • solid solution denotes a solid-state solution of one or more solutes in a solvent, wherein the mixture remains in a single homogenous phase.
  • the water- dispersible or water-soluble carrier is selected from the group consisting of modified or unmodified carbohydrates, preferably monomeric, oligomeric or polymeric carbohydrates, preferably modified or unmodified monomeric, oligomeric or polymeric monosaccharides, or straight or branched oligosaccharides or polysaccharides; wax; gum; organic or inorganic acids or bases, or a salt thereof; surfactants; synthetic polymers; modified or unmodified silica; mineral pharmaceutical excipients or a combination thereof; preferably the carrier is crystalline.
  • composition according to any of the preceding items, wherein the carrier is sucrose, maltose, lactose, glucose, mannose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, a starch or modified starch, such as pregelatinized starch, corn starch, potato starch, or maize starch; an alginate, gelatin, carrageenan, dextran, maltodextran, dextrates, dextrin, polydextrose, or tragacanth; acacia, guar gum, xanthan gum; cellulose such as carboxymethylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, powdered cellulose, or microcrystalline cellulose; polyacrylic acid, modified or unmodified alginate or chito
  • composition according to item (6) wherein the carrier is selected from the group consisting of lactose, sucrose, maltose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, starch and cellulose, preferably lactose, maltose, mannitol, sorbitol, starch and cellulose, more preferably lactose and cellulose, yet more preferably the carrier is lactose.
  • the carrier is selected from the group consisting of lactose, sucrose, maltose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, starch and cellulose, preferably lactose, maltose, mannitol, sorbitol, starch and cellulose, more preferably lactose and cellulose, yet more preferably the carrier is lactose.
  • the weight ratio of the at least one hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 1 1 : 1 w/w or wherein the weight ratio can even be 99: 1 w/w to 4: 1 w/w if the active pharmaceutical ingredient is selected from the group consisting of phosphodiesterase inhibitors, preferably phosphodiesterase II I inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives; or wherein the weight ratio 99:1 w/w to 4:1 w/w if a hyperbranched polyesteramide, preferably a hyperbranched polyesteramide having tertiary amine end groups or having hydroxyl end groups is used as the hyperbranched polymer, and c) a hydrophilic or hydrophobic carrier, preferably a hydrophilic carrier, more preferably the carrier is crystalline.
  • the hyperbranched polymer and the at least one pharmaceutically active ingredient form a solid dispersion or a solid solution, preferably the solid dispersion or solid solution and the pharmaceutically active ingredient is combined with the solid or dissolved carrier.
  • the carrier is a solid carrier.
  • the carrier may be combined with the solid dispersion or solid solution by using mixing, high shear mixing, spray drying, fluid bed granulation or freeze drying.
  • the solution of step b) is sprayed onto the carrier particles.
  • a solid dispersion is formed between the hyperbranched polymer and the at least one pharmaceutically active ingredient.
  • composition (10) The pharmaceutical composition according to any one of the preceding items, wherein the amount of carrier included in the composition is from 10 % to 90 %, preferably from 30 % to 60 %, more preferably from 50 % to 80 %, yet more preferably from 70 % to 80 % based on the weig ht of the pharmaceutical composition and powder or granulate, respectively.
  • composition, powder or granulate according to any one of the preceding items, wherein the at least one pharmaceutically active ingredient is selected from the group consisting of glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadalafil, atovaquone and indapamide, preferably glimepiride, pimobendan, tadalafil, atovaquone and indapamide, more preferably the pharmaceutically active ingredient is glimepiride.
  • the at least one pharmaceutically active ingredient is selected from the group consisting of glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadalafil, atovaquone and indapamide, preferably glimepiride, pimobendan, tadalafil, atovaquone and indapamide, more preferably the pharmaceutically active ingredient is glimepiride.
  • said additional pharmaceutically active ingredient is selected from the group consisting of the thiazolidinone class, biguanide class, statin class, fibrate class, thiazide class, and acarbose, miglitol, voglibose, orlistat, sibutramine, rimonabant, exenatide and pramlintide; preferably said additional pharmaceutically acive ingredient is selected from the biguanide class, thiazolidinone class and thiazide class; more preferably it is selected from the thiazolidinone class.
  • Pharmaceutically active ingredients from the thiazolidinone class are for example pioglitazone, rivoglitazone, rosiglitazone, troglitazone.
  • Preferred pharmaceutically active ingredients from the thiazolidinone class are pioglitazone or rosiglitazone, more preferably pioglitazone.
  • Pharmaceutically active ingredients from the biguanide class are for example phenformin, buformin or metformin, preferably metformin.
  • Pharmaceutically active ingredients from the statin class are for example atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin.
  • Preferred pharmaceutically active ingredients of the statin class are atorvastatin, pravastatin, rosuvastatin or simvastatin, more preferably rosuvastatin.
  • the pharmaceutical composition, powder or granulate according to the present invention comprises one or more pharmaceutically active ingredients according to item (1 1 ) and one or more pharmaceutically active ingredients according to item (12).
  • the pharmaceutical composition according to the present invention comprises one pharmaceutically active ingredient selected from the group according to item (1 1 ) and one pharmaceutically active ingredient selected from the group according to item (12).
  • the constituents form a solid dispersion.
  • the pharmaceutical composition, powder or granulate according to any of the preceding items, wherein the pharmaceutical composition, powder or granulate is optionally mixed with a pharmaceutically acceptable excipient.
  • the excipients are fillers such as lactose, mannitol, cellulose derivatives, and sucrose; disintegrators such as crosscarmellose sodium, calcium carbonate, carboxymethylcellulose calcium, binders such as polyvinylpyrrolidone; lubricants such as magnesium stearate, stearic acid, and silicium dioxide; fragrants such as vanilla extract; colorants such as titanium dioxid; sweeteners such as saccharine; coating polymers such as hydroxypropylmethylcellulose; or vehicles such as water and organic solvents.
  • the pharmaceutical composition, powder or granulate do not contain a surfactant (surface active agent).
  • compositions comprising the pharmaceutical composition, powder or granulate according to any one of the preceding items, wherein preferably the pharmaceutical dosage form is a solid dosage form, preferably in the form of a pellet, a tablet, a capsule, a sachet, preferably the dosage form is a tablet.
  • the organic solvent is removed in a first process forming a solid dispersion and/or a solid solution, preferably a solid dispersion. More preferably, the organic solvent is removed by using mixing, spray-drying, fluid-bed granulation or freeze drying, more preferably spray-drying and fluid-bed granulation.
  • step b) or step c) removing the solvent and preparing a powder or granulate, wherein step b) or step c) further comprises combining the mixture with a hydrophilic or hydrophobic carrier, preferably a hydrophilic carrier, more preferably a crystalline carrier.
  • a hydrophilic or hydrophobic carrier preferably a hydrophilic carrier, more preferably a crystalline carrier.
  • the organic solvent is removed and effectively allows forming a solid solution and/or a solid dispersion, preferably a solid dispersion.
  • organic solvent is selected from the group consisting of C 2 -C 4 alkanols, such as ethanol, n-propanol, isopropanol, n- butanol, isobutanol; aliphatic or alicyclic ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofurane; ketone, such as acetone, methyl ethyl ketone; dimethylsulphoxide and dimethylformamide; or mixtures thereof.
  • C 2 -C 4 alkanols such as ethanol, n-propanol, isopropanol, n- butanol, isobutanol
  • aliphatic or alicyclic ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydr
  • step b) The process according to any of items (18)-(20), wherein in step b) a water- dispersible or water-soluble pharmaceutically acceptable carrier, preferably a carrier as defined in any of the above items, is added.
  • step c) The process according to any of items (18)-(21 ), wherein mixing can be carried out during step b) and or step c).
  • step c) is performed by using mixing, high shear mixing, spray drying, fluid bed granulation or freeze drying.
  • drying can be carried out in a vacuum oven at a temperature of below 60°C, preferably below 50°C, most preferably at 40°C or below.
  • the additional pharmaceutically active ingredient is selected from the thiazolidinone class, biguanide class, statin class, fibrate class, thiazide class, acarbose, miglitol , voglibose, orlistat, sibutramine, rimonabant, exenatide and pramlintide, it is preferably selected from biguanide class, thiazolidinone class and thiazide class, more preferably it is selected from thiazolidinone class.
  • a process for preparing a solid dispersion and/or solid solution of a hyperbranched polymer and at least one pharmaceutically active ingredient comprising the steps of:
  • step b) providing the solid dispersion and/or solid solution from the dispersion/solution of step a) by using high shear mixing, spray drying or fluid bed granulation, wherein the mixture in step a) or the solid dispersion and/or solid solution of step b) is optionally combined with a hydrophilic or hydrophobic carrier, preferably a hydrophilic carrier, more preferably a crystalline carrier.
  • a hydrophilic or hydrophobic carrier preferably a hydrophilic carrier, more preferably a crystalline carrier.
  • polyesteramide hyperbranched polymers preferably a polyester hyperbranched polymer having tertiary amine or hydroxyl end groups
  • the weight ratio of the hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 1 1 :1 w/w or wherein the weight ratio can even be 99:1 w/w to 4:1 w/w if the active pharmaceutical ingredient is selected from the group consisting of phosphodiesterase inhibitors, preferably phosphodiesterase II I inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives.
  • a hydrophilic or hydrophobic carrier for the preparation of a pharmaceutical composition
  • a pharmaceutically active ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives, preferably a non-thiazide sulphonamide, in mixture with at least one hyperbranched polymer.
  • hydrophilic carrier for the preparation of a pharmaceutical composition
  • a pharmaceutically active ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives, preferably a non-thiazide sulphonamide, in mixture with at least one hyperbranched polymer.
  • an active pharmaceutical ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives for the preparation of a pharmaceutical composition comprising at least one hyperbranched polymer, wherein the at least one pharmaceutically active ingredient exhibits a solubility in an aqueous media at pH 6.8 and 37° C of less than 1 mg/ml, and wherein the weight ratio of the at least one hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 4:1 w/w.
  • the pharmaceutical ingredient is selected from the group consisting of pimobendan, tadalfil, indapamide, glimepiride, and atovaquone.
  • API active pharmaceutical ingredient
  • the pharmaceutical composition according to the present invention provides for the concentration of pharmaceutically active ingredient that is needed to be effective in the physiological environment.
  • the solubility of said API is sufficiently high to reach the required concentration at the target location, such as the gastrointestinal tract, or to achieve the necessary blood concentration upon absorption. Therefore, the pharmaceutical composition according to the present invention does not need to contain a larger amount of an API, which normally would be needed in order to compensate the poor solubility of the API in aqueous solution. This, in turn, leads to a pharmaceutical composition that does not exhibit an increased size, which could affect negatively patients ' compliance.
  • the pharmaceutical composition according to the present invention as well as the process for the preparation of such a pharmaceutical composition is much more cost effective: Based on the enhanced solubility of the API being present in the pharmaceutical composition, less amount of API is necessary in order to provide for the desired effective API concentration on the target site.
  • solubility of poorly soluble active pharmaceutical ingredients can particularly be increased, provided that a specific weight ratio of the hyperbranched polymer and the at least one active pharmaceutical ingredient is used.
  • the APIs according to the invention which are selected from the group consisting of phosphodiesterase inhibitors, preferably phosphodiesterase III inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives, particularly provide for a very high dissolution rate in the first 5 minutes of the dissolution test.
  • mixtures of hyperbranched polymers with the APIs according to the invention provide for a rapid dissolution which leads to an advantageously fast increase of the drug plasma level in the subject to be treated with a pharmaceutical composition containing this mixture.
  • a particu larly preferred AP I is pimobendan which showed the highest increase of dissolution rate (compare Figure 7).
  • the solubility can be further increased if the hyperbranched polymer and the at least one active pharmaceutical ingredient form a solid dispersion.
  • polyesteramide hyperbranched polymers in particular polyesteramide hyperbranched polymers having tertiary amine or hydroxyl end groups, are particularly advantageous for increasing the solubility of an API (compare Figures 3 and 4).
  • the use of a polyesteramide having hydroxyl end groups e.g. Hybrane ® S1200
  • is preferred with respect to obtaining a pharmaceutical composition, powder, granulate or pharmaceutical dosage form having a very low hygroscopicity see Figure 8 which shows the lowest water uptake if Hybrane ® S1200 is used as the hyperbranched polymer).
  • powders or granulates comprising a specific weight ratio of the hyperbranched polymer and the at least one active pharmaceutical ingredient and having improved properties (e.g. low hygroscopicity) can be prepared when using hydrophilic or hydrophobic carriers, preferably hydrophilic carriers (see Figure 8).
  • hydrophilic or hydrophobic carriers preferably hydrophilic carriers
  • technical contribution again allows applying a more general weight ratio of hyperbranched polymer to API.
  • stability and solubility of the API can be increased even more in case a crystalline carrier is used. This is in particular advantageous if the pharmaceutical composition should be in the form of a powder or granulate or a dosage form.
  • the ratio of hyperbranched polymer/at least one active pharmaceutical ingredient should at least be 1 1 :1 or in case of specific APIs at least 4:1 , in order to provide a significantly enhanced solubility.
  • the solubility decreases.
  • solubility of the respective API increases because the previously unassociated, poorly soluble active pharmaceutical ingredient interacts with the hydroxyl, ester, amido and/or carboxyl groups of the hyperbranched polymers.
  • a weight ratio of hyperbranched polymer: API of more than 99:1 there might be a situation when H-bonds between the hyperbranched polymer itself predominates over the intermolecular interactions between the active ingredient and the polymer, leading to closing the polymer and not contributing any more to enhancing the solubility of the active ingredient.
  • the interactions between the molecules of the pharmaceutically active ingredients can lead to a crystallization of the pharmaceutically active ingredient which reduces the solubility.
  • compositions are biocompatible and suitable to be used in living organisms.
  • hyperbranched polymers As can be seen for example for many cationic systems, including liposomes and micelles with surface groups bearing cationic charge, these cationic systems can readily damage cell membranes, leading to cell lysis. Hence, the issue of low-toxicity is relevant for hyperbranched polymers, as for any other prospective pharmaceutical excipient, before considering their use. Due to the biocompatible properties of the hyperbranched polymers, they are suitable for use in mammals. In particular hyperbranched polyesteramides have both amides as well as ester linkages which attributes to amphiphilicity and biodegradability. Hyperbranched polyesteramides possess the excellent mechanical properties of polyamides and the biodegradability of polyester.
  • polyesteramides Owing to the polar nature of amide groups and their ability to form hydrogen bonds, these polymers exhibit good thermal and mechanical properties even at low molecular weight. On the other hand, hydrolytically degradable ester bond provides biodegradability to the polymer. Branching of polyesteramides have been reported to substantially enhance hydrolysis both in alkaline and in phosphate buffered saline solution, exceptionally reducing the burden to the living organism.
  • compositions, powders or granulates comprise at least one hyperbranched polymer, preferably the specific hyperbranched polymers as described herein.
  • hyperbranched polymer generally denotes very generally polymers known as dendritic polymers, dendrimers, arborol, cascade, cauliflower or star polymers, polydisperse hyperbranched polymers, dendrigraft polymers, or other high molecular weight polymers, which all have specific branched structure containing a center atom or a molecule, which can be monomeric or polymeric, from where three or more chains emanate. Hyperbranched polymers are thus distinguishable from linear polymers, copolymers or graft polymers, crosslinked linear polymers or comb polymers.
  • hyperbranched polymers within the meaning of the invention possess a large number of terminal functional groups.
  • intermolecular interactions between the hyperbranched polymers depend largely on the types of the terminal functional groups, resulting in large variations in the glass transition temperature, the solubility, the thin film forming property, or the like.
  • such a hyperbranched polymer has characteristics that no general li near polymer has.
  • the hydrodynamic characteristics of hyperbranched polymers significantly differ from those of linear polymers with similar chemical structure of repeating units and the same molecular weight.
  • hyperbranched or dendritic polymers One of the most important characteristics of hyperbranched or dendritic polymers is their inability to crystallize or entangle the polymer chain regardless of their molecular weights. The miscibility of these polymers cannot be accurately predicted with current understanding on the rules of linear polymer, since the branched structu re affects interpolymer chain interaction.
  • the hyperbranched polymer can have a large number of functional groups also along the branched chains. According to the invention, it is preferred to use hyperbranched polymer comprising hydroxyl groups, ester groups, amido groups and/or carboxyl groups as terminal functional groups (end groups).
  • the hyperbranched polymer comprises either ester groups or amido groups or both, further preferred the hyperbranched polymer is a polyesteramide, further preferred polyesteramides having tertiary amine end groups. It has also been found that polyesteramide hyperbranched polymers, in particular polyesteramide hyperbranched polymers having tertiary amine or hydroxyl end groups, are particularly advantageous for increasing the solubility of an API when compared to general linear polymer (compare Figure 1 B and Figures 3 and 4).
  • hyperbranched polymers can be synthesized according to any suitable method that is known to a person skilled in the art.
  • the hyperbranched polymers are synthesized by coupling the same or different monomers to the center atom or a molecule in one or more runs, wherein at least some monomers have three or more functional groups, making subsequent coupling reactions possible at the unreacted terminal functional groups, which leads to the formation of branched extensions.
  • a monomer within the meaning of the present invention is a small molecule that can become chemically bonded to other monomers in order to form polymers.
  • Monomers can be either synthetic, such as hydrocarbons, or natural, such as amino acids. The aforementioned method can be used to generate different degrees of random or ordered hyperbranched polymers.
  • the terminal functional groups of the hyperbranched polymers can be tailored by subsequent substitution or addition reactions for reasons such as to increase the number of functional groups or to substitute them, and covalently link the polymer with another molecule, i.e. for delivery of nutriments, vitamins, or active pharmaceutical ingredients.
  • the use polyethylenglycols as polymer chains allows for protecting the hyperbranched polymer from being detected by the mononuclear phagocyte system when administered to humans or animals. It is also possible to introduce recognizable groups complementary to a receptor or to a tissue, or to introduce moieties facilitating the transport of the hyperbranched polymer through the cell membrane.
  • the preferred hyperbranched polymers used according to the present invention are polydisperse hyperbrached polymers, otherwise also known to belong to dendritic group of polymers as one of the subclasses (beside dendrimers and dendrigraft polymers).
  • Dendrimers for example are monodisperse cascade branched macromolecules with an exponential growth of terminal end groups per synthesized generation. In order to obtain monodisperse perfect structures the products have to be purified after each synthetic step, which renders the synthesis costly and limits their use to high added value products.
  • the dendrimers have a low polydispersity, rather they are monodisperse.
  • the Mw/Mn ratio of dendrimers is around 1 .0, preferably bellow 1 .01 and their molecular weight can be predicted mathematically. Contrary to dendrimers the polydisperse hyperbranched polymers are obtained by random condensation reactions causing that control over the molecular weight and branching is only limited. Polydisperse hyperbranched polymers have the Mw/Mn ratio of over 1 .1 , preferably around 2, but can be even more than 3, like for example 5. Polydispersity of a polymer sample is a measure of the distribution of molecular mass in a said polymer sample. It is expressed by the weight average molecular weight (Mw) divided by the number average molecular weight (Mn).
  • the value of polydispersity can be equal to or greater than 1 . More homogenous sample in terms of having polymer chains of more uniform length has polydispersity value closer to unity (1 ).
  • the number average molecule weight (Mn) of preferred polydisperse polybranched polymers lies in a range of 400 to 100000 g/mol, preferably is between 700 to 60000 g/mol, more preferably between 1000 to 5000 g/mol, particularly is around 1200 g/mol or around 1600 g/mol.
  • hyperbranched polymers according to the present invention are hyperbranched polyimines, hyperbranched polyurethanes, hyperbranched polyamides, hyperbranched polyesteramines, hyperbranched polyesteramides, particulary preferred are hyperbranched polyesteramines and hyperbranched polyesteramides, even further preferred are hyperbranched polyesteramides. It is understood that said hyperbranched polymers can have different monomers introduced in their structure and the terminal functional groups can optionally be modified.
  • the hyperbranched polyesteramide i.e. the preferred hyperbranched polymer according to the present invention, are obtained for example by first providing a monomer by reacting a cyclic anhydride (e.g.
  • succinic, hexahydrophthalic or phthalic anhydride with a diisopropanol amine, yielding a tertiary amide with one COOH and two OH groups, and then subjecting it to polycondensation via an oxazolinium intermediate in bulk at relatively mild conditions in the absence of catalyst.
  • anhydrides, and modification with several types of end groups By varying and combining anhydrides, and modification with several types of end groups, a large variety of structures with concomitant properties can be obtained.
  • Two examples representing hydrophilic, water soluble hypebranched polyesteramides are Hybrane S1200 (terminal hydroxyl groups) and HA1690 (terminal tertiary amine groups).
  • compositions, powders or granulates further comprise at least one active pharmaceutical ingredient having a low solubility.
  • solubility in an aqueous media at pH 6.8 and 37° C of less than 1 mg/ml.
  • Solubility as meant herein is measured using USP apparatus 2 (U.S. Pharmacopoeia 32-NF27) with agitation at 75 RPM in the dissolution medium of a phosphate buffer maintained at pH 6.8 and 37° C.
  • USP apparatus 2 U.S. Pharmacopoeia 32-NF27
  • Such low solubility makes preparing a useful pharmaceutical composition of acceptable size and efficacy especially difficult.
  • the pharmaceutical composition according to the present invention contains at least one pharmaceutically active ingredient exhibiting solubility in aqueous media at pH 6.8 and 37°C of less than 1 mg/ml. In a preferred embodiment, this is irrespective of the pharmacological effect it might have or ailment it is used to prevent or treat.
  • the solubility of this active pharmaceutical ingredient is measured by using only the active pharmaceutical ingredient, i .e. the active pharmaceutical ingred ient is not m ixed with any additives l ike e.g . hyperbranched polymers.
  • the solubility of the active pharmaceutical ingredient in an aqueous media at pH 6.8 and 37° C is in a range of equal to or less than 1 mg/ml and equal to or more than 0.2 mg/ml, further preferred in a range of equal to or less than 1 mg/ml and equal to or more than 0.3 mg/ml, even further preferred in a range of equal to or less than 1 mg/ml and equal to or more than 0.4 mg/ml.
  • Preferred active pharmaceutical ingredients are selected from the group consisting of phosphodiesterase inhibitors , p r e f e r a b l y phosphodiesterase III inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives.
  • a preferred phosphodiesterase III inhibitor is pimobendan, a preferred phosphodiesterase V inhibitor is tadalfil; a preferred non-thiazide sulphonamide is indapamide; sulfonylurea derivatives that are insulin secretion enhancers are acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide, gliquidone, glyclopyramide, glimepiride, glixosepid, glimidine, glypinamide, glyhexamide, glibuzole or glybuthiazole, more preferably are glimepiride, gliclazide, glipizide and glibenclamide; and a preferred hydroxy-1 ,4-naphthoquinone derivative atovaquone, which has an antiprotozoal activity.
  • solubility of the aforementioned APIs preferably that of phosphodiesterase III inhibitors, e.g. pimobendan
  • phosphodiesterase III inhibitors e.g. pimobendan
  • the solubility of the aforementioned APIs can be particularly strongly increased, even if the weight ratio of hyperbranched polymer/API is only 4:1 or higher, for example 50:1 (compare Figure 7).
  • Pimobendan and levosimendan are selective phosphodiesterase III inhibitors used in the management of heart failure.
  • Tadalafil is a phosphodiesterase E5 inhibitor and can be used for treating erectile dysfunction or pulmonary arterial hypertension. Atovaquone is known of its anti-yeast and antiparasitic activity.
  • non-thiazide sulphonamides preferably indapamide
  • a hydrophilic or hydrophobic carrier preferably a hydrophilic carrier
  • the solubility in aqueous media of pH around 7 (at least glimepiride has a pH-dependent solubility) of the respective compounds is as follows: glimepiride 0.001 mg/ml; gliclazide 0.05 mg/ml; glipizide 0.037 mg/ml; glibenclamide 0.06 mg/ml; pimobendan 0.21 mg/ml; tadalafil 0.1 1 mg/ml; atovaquone 0.003 mg/ml; indapamide 0.7 mg/ml.
  • the increase in solubility of the active ingredient in aqueous media under the above indicated conditions is 10, 50, 55, 100 and 140-fold, respectively, compared to the solubility of the pure API.
  • the highest increase in solubility can be achieved if the active pharmaceutical ingredient is selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives, an even further increase can be achieved when using glimepiride, pimobendan, tadalafil, atovaquone or indapamide as API.
  • compositions, powders or granulates according to the invention comprise the hyperbranched polymer/API in specific weight ratios.
  • the weight ratio of hyperbranched polymer/active pharmaceutical according to the invention is 99:1 to 1 1 :1 .
  • the weight ratio is 99:1 to 14:1 , further preferred the weight ratio is 99:1 to 17: 1 , even further preferred, the weight ratio is 99: 1 to 18:1 .
  • the weight ratio is 80:1 to 1 1 :1 , further preferred, the weight ratio is 55:1 to 1 1 :1 , even further preferred, the weight ratio is 24:1 to 1 1 :1 .
  • the weight ratio is 80:1 to 14:1 , further preferred, the weight ratio is 55:1 to 17:1 , even further preferred, the weight ratio is 24:1 to 18:1.
  • the weight ratio of polybranched polymer and said active pharmaceutical ingredient is 80:20 w/w to 98:2 w/w, preferably 88:12 w/w to 98:2 w/w, more preferably 90:10 w/w to 98:2 w/w, yet more preferably 93:7 w/w to 98:2 w/w, particularly 98:2 w/w to 95:5 w/w, further preferably 98:2 w/w to 95:2 w/w.
  • the weight ratio of hyperbranched polymer/API should be 1 1 :1 or above.
  • the solubility of the specific active pharmaceutical ingredients selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4- naphthoquinone derivatives can also be highly increased when using a weight ratio of hyperbranched polymer/API of as low as 4:1 (or above).
  • the weight ratio can be as low as 4:1 (or above) if the specific polyesteramide hyperbranched polymers as described herein are used.
  • the preferred weight ratios of 1 1 :1 and above as defined herein represent the preferred embodiments of the invention independent of the constituents which are used.
  • compositions, powders and granulates comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient exhibiting solubility in an aqueous media at pH 6.8 and 37° C of less than 1 mg/ml
  • the pharmaceutical compositions, powders and granulates comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient exhibiting solubility in an aqueous media at pH 6.8 and 37° C of less than 1 mg/ml can be prepared by providing both constituents in an organic solvent in the specific weight ratios as defined herein and removing the solvent. It has been found that the constituents get intimately mixed and thus probably develop the highest possible number of intermolecular interactions between the polymer and the active ingredient if the solid dispersion is provided from the dispersion/solution of the at least one hyperbranched polymer and the at least one API in the organic solvent by using known techniques such as for example high shear mixing, spray drying or fluid bed granulation.
  • the API is completely dissolved in the organic solvent.
  • a hydrophilic or hydrophobic carrier specifically a hydrophilic carrier, in particular if a powder or granulate comprising the API is prepared.
  • a solution or dispersion e.g. a dispersion containing solid API and/or solid carrier particles, is used for preparing a mixture or solid dispersion according to the invention, a person skilled in the art considering the teaching provided herein can choose a suitable method for preparation.
  • solid dispersion refers to a homogenous mixture of active pharmaceutical ingredient (particles) in the hyperbranched polymer. Active pharmaceutical ingredient is dissolved or dispersed in the polymer.
  • a solid solution is a solid-state solution of one or more solutes in a solvent (in this case the "solvent" is represented by the hyperbranched polymer).
  • solvent in this case the "solvent” is represented by the hyperbranched polymer.
  • Such a mixture is considered a solution rather than a compound when the structure of the solvent remains unchanged by addition of the solutes, and when the mixture remains in a single homogeneous phase.
  • the at least one hyperbranched polymer and the at least one active pharmaceutical ingredients are in contact with each other, preferably over a large surface area.
  • the solid dispersion of components can be obtained by using the processes as described herein.
  • the solid dispersion of the active pharmaceutical ingredient and hyperbranched polymer is obtained by using the solvent method, wherein both the active pharmaceutical ingredient and the hyperbranched polymer are completely dissolved in an organic solvent, wherein upon removal of the organic solvent the solid dispersion is obtained.
  • Techniques allowing fast removal of the organic solvent appear to assist in the formation of association and/or complex contacts between the polymer and the API, optionally further enhanced by the presence of hydrophilic or hydrophilic carrier, particularly by the presence of hydrophilic carrier.
  • removal of the organic solvent is accomplished over multiple days, preferably over 24 hours, more preferably within 10 hours and most preferably within 1 hour.
  • AP I-API association, API secondary particle formation, and API crystallization can be inhibited by such fast solvent removal, all such phenomena otherwise counter-acting the desirable association and/or complexation as disclosed herein.
  • the removal of the solvent is efficiently carried out by using known techniques like mixing, high shear mixing, spray drying, fluid bed granulation or freeze drying. Preferably, high shear mixing, spray drying or fluid bed granulation are used.
  • the solution or dispersion of hyperbranched polymer/API is preferably sprayed onto the carrier particles by using known techniques.
  • hyperbranched polymers are water soluble through terminal functional groups and are extremely hygroscopic because of their amorphous form.
  • a hygroscopic hyperbranched polymer When a hygroscopic hyperbranched polymer is exposed to the atmosphere, water from vapour migrates into/onto the polymer, and some of the water molecules bind to the polymer chains by intermolecular forces.
  • Hygroscopicity of a hyperbranched polymer can be measured by methods known to a person skilled in the art. Mainly, such methods comprise determining the mass of a small amounts of a sample (i.e. 5 -10 mg) as a function of time, while varying the controlled relative humidity and/or temperature in the environment.
  • the hygroscopic nature of the hyperbranched polymer causes the pharmaceutical composition comprising the hyperbranched polymer and the active pharmaceutical ingredient to attract water and, e.g. when having a pharmaceutical composition in powder form, the particles of the powder change shape and eventually cause the composition to liquefy.
  • the properties of a pharmaceutical composition which is e.g. in the form of a powder, do not change upon storage.
  • compositions according to the invention preferably comprise a carrier.
  • the powders or granulates according to the invention also comprise a carrier.
  • a water-dispersible or water-soluble pharmaceutically acceptable carrier preferably a hydrophilic or hydrophobic carrier, more preferably a hydrophilic carrier, particularly preferable a crystalline carrier
  • a hydrophilic carrier particularly preferable a crystalline carrier
  • a crystalline hydrophilic carrier particularly preferred is a crystalline hydrophilic carrier.
  • the properties of the inventive pharmaceutical compositions remain steady in terms of adequate flowability, chemical stability and compressibility, in particular when using a crystalline carrier. Flowability, chemical stability or compressibility can be determined by using known methods in the art, for example the methods explained in the European Pharmacopoeia, 6th Edition.
  • water-dispersible or water-soluble carrier preferably a hydrophilic, preferably a crystalline, carrier
  • the pharmaceutical composition is suitable for molding processes.
  • carriers in particular crystalline carriers, in powders, granulates, pellets, pills, tablets, capsules thus increases the shelf life of the dosage form.
  • water-dispersible or water-soluble pharmaceutically acceptable carrier is construed as any pharmaceutically acceptable excipient in a solid or semi-solid form, which can be dispersed or dissolved in water at 37 °C
  • Said carrier can be for example a modified or unmodified carbohydrate, which can be monomeric, oligomeric or polymeric; a wax; a gum; an organic or inorganic acid or base, or salt thereof, a surfactant, a synthetic polymer, a modified or unmodified silica, a mineral pharmaceutical compound such as calcium phosphate, calcium sulfate, calcium chloride, magnesium carbonate, magnesium oxide, sodium chloride, magnesium aluminum silicate, polacrilin potassium, talc, aluminum hydroxide, aluminum oxide, or a combination thereof.
  • a modified or unmodified carbohydrate which can be monomeric, oligomeric or polymeric
  • a wax can be monomeric, oligomeric or polymeric
  • a gum an organic or inorganic acid or base, or salt thereof, a surfactant, a synthetic polymer, a modified or unmodified silica, a mineral pharmaceutical compound such as calcium phosphate, calcium sulfate, calcium chloride, magnesium carbonate, magnesium
  • Said carrier can also be for example carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose acetate, cellulose acetate phthalate, ceresin, cetyl alcohol, chitosan, cellulose, ethylcellulose, gelatin, glucose, glyceryl behenate, glyceryl palmitostearate, methylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, croscarmellose sodium, hydroxypropyl cellulose, isomalt, maltitol, mannitol, kaolin, lactitol, maltodextrin, polydextrose, dextrates, dextrin, dextrose, methylcellulose, polydextrosepoly(dl-lactic acid), polyethylene oxidepolyvinyl, acetate phthalate, polyvinyl alcohol, shell
  • the carrier is a hydrophilic carrier, which is preferably selected from the group consisting of sugars and carbohydrates, preferably the carrier is selected from the group consisting of modified or unmodified monosaccharides, straight or branched oligosaccharides, and straight or branched polysaccharides, or mixtures thereof.
  • the carrier is selected from the group consisting of lactose, sucrose, maltose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltitol, starch, or cellulose, preferably lactose, maltose, mannitol, sorbitol, starch and cellulose, more preferably lactose and cellulose, yet more preferably is lactose.
  • a pharmaceutically acceptable carrier contributes to the formation a powder or granulate.
  • the amount of carrier included in the pharmaceutical composition should preferably be from 10 % to 90 %, preferably from 30 % to 60 %, more preferably from 50 % to 80 %, yet more preferably from 70 % to 80 % based on the total weight of the pharmaceutical composition.
  • the carrier prevents the composition from increasing in weight due to water absorption of water originating from the environment, e.g. air.
  • the carrier prevents the particles of the composition from growing in size and enables it to be used essentially unchanged over time.
  • the beneficial effect of limited size distribution is improved flowability, particularly when the invention is practiced on a large scale.
  • a hydrophilic carrier as defined above is used.
  • the carrier can be in particulate form and/or crystalline form.
  • the carrier is used in crystalline form.
  • the protective effect towards the composition in this case is most pronounced, probably because the carrier in crystalline form is less subjected to hygroscopicity. It has been unexpectedly found that the hygroscopicity is reduced even if the solid dispersion according to the invention is deposited on the carrier surface.
  • the carrier is added to the hyperbranched polymer and the pharmaceutically active ingredient only after the solvent has been already removed, or at least partly removed.
  • This can be achieved simply by mixing obtained solid dispersion comprising the hyperbranched polymer and the pharmaceutically active ingredient with the carrier. Additional option is to remove solvent while the carrier is being combined with the two constituents. An example where this takes place is when the solution/dispersion of hyperbranched polymer and API is sprayed onto the carrier particles, leading to evaporation and thus removal of the solvent while the carrier is being coated by the arising solid dispersion.
  • the skilled person would understand that the order or combination of steps where the carrier is added can be chosen as desired, i.e.
  • the carrier can be added simultaneously or sequentially to providing the at least one hyperbranched polymer and the at least one pharmaceutically active ingredient to organic solvent or to removing the solvent.
  • the carrier preferably in crystalline form, can be even first added into the solution/dispersion and then again after solvent removal.
  • the solution/dispersion of hyperbranched polymer and API is sprayed onto the carrier particles as described herein.
  • X-ray powder diffraction analysis can be carried out.
  • the pharmaceutical composition contains a crystalline carrier.
  • the pharmaceutical composition is amorphous and does not represent a pharmaceutical composition according to the preferred embodiment of the invention.
  • Characteristic peaks of a crystalline carrier can be easily obtained from publicly available data bases by a person skilled in the art. It is also possible to first carry out an X-ray powder diffraction analysis of the crystalline carrier itself in order to identify the characteristic peaks of the carrier material.
  • peaks can be determined.
  • the pharmaceutical composition can firstly be analyzed to find out which specific carrier material has been used. The characteristic peaks of this carrier material can then be obtained from literature or routine experiments.
  • additional excipients can be used. Such excipients can be added together with the carrier, in particular prior to the solvent removal (according to the solvent method as described herein) or after the mixture, preferably solid dispersion, of hyperbranched polymer and API has been prepared in a solid form. Pharmaceutical excipients which also represent carriers according to the above definition will be referred to as carriers in case they are added to the mixture prior to solvent removal.
  • excipients are used after the preparation of the solid dispersion, e.g. if the excipients are added to the coating of a tablet, such excipients are not regarded as carriers.
  • some of the carriers as indicated above might also be suitable as pharmaceutical excipients which are used after the solvent removal.
  • Suitable excipients are any conventionally used pharmaceutically acceptable excipients.
  • the excipients can be fillers (lactose, mannitol, cellulose derivatives, sucrose, etc.), disintegrators (crosscarmellose sodium, calcium carbonate, carboxymethylcellulose calcium etc.), binders (polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, stearic acid, silicium dioxide, etc.), fragrants, colorants (titanium dioxide, etc.), sweeteners (saccharine, etc.), coating polymers (hydroxypropylmethylcellulose, etc.), or vehicles (water, organic solvents, etc.).
  • the pharmaceutical compositions, powders or granulates further comprise another active pharmaceutical ingredient.
  • an additional active ingredient may be chosen to complement the pharmacological activity of the first active pharmaceutical ingredient, such as those mentioned above, in terms of providing an additive effect, a synergistic effect, a complementary effect, reduction of side effects, or the like.
  • the additional active pharmaceutical ingredient is selected from the thiazolidinone class, biguanide class, statin class, fibrate class, thiazide class, acarbose, miglitol, voglibose, orlistat, sibutramine, rimonabant, exenatide and pramlintide, it is preferably selected from biguanide class, thiazolidinone class and thiazide class, more preferably it is selected from thiazolidinone class.
  • Active pharmaceutical ingredients from the thiazolidinone class are for example pioglitazone, rivoglitazone, rosiglitazone, troglitazone.
  • Preferred active pharmaceutical ingredients from the thiazolidinone class are pioglitazone or rosiglitazone, more preferably pioglitazone.
  • Active pharmaceutical ingredients from the biguanide class are for example phenformin, buformin or metformin.
  • a preferred biguanide class active pharmaceutical ingredient is metformin.
  • Active pharmaceutical ingredients from the statin class are for example atorvastatin , cerivastatin , fluvastatin , lovastatin , mevastatin , pitavastatin, pravastatin, rosuvastatin or simvastatin.
  • statin class active pharmaceutical ingredients are atorvastatin, pravastatin, rosuvastatin or simvastatin, more preferably rosuvastatin.
  • Active pharmaceutical ingredients from the fibrate class are for example bezafibrate, ciprofibrate, clofibrate, gemfibrozil or fenofibrate.
  • Preferred fibrate class active pharmaceutical ingredients are gemfibrozil or fenofibrate, more preferably fenofibrate.
  • Active pharmaceutical ingredients from the tiazide class are for example chlorothiazide, or hydrochlorothiazide, preferably hydrochlorothiazide.
  • the pharmaceutical composition, powder or granulate comprises at least one active pharmaceutical ingredient selected from the group consisting of glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadalafil, atovaquone and indapamide and at least one hyperbranched polymer, wherein the at least one active pharmaceutical ingredient and hyperbranched polymer are mixed, preferably intimately mixed, at a weight ratio as indicated above, e.g.
  • the at least one active pharmaceutical ingredient is glimepiride, pimobendan, tadalafil, atovaquone or indapamide, preferably is glimepiride or pimobendan, more preferably is glimepiride.
  • said pharmaceutical composition further comprises a water- dispersible or water-soluble pharmaceutically acceptable carrier, preferably lactose.
  • One embodiment of the present invention relates to a powder or granulate comprising a) at least one hyperbranched polymer,
  • the weight ratio of the at least one hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 1 1 :1 w/w or wherein the weight ratio can even be 99: 1 w/w to 4: 1 w/w if the active pharmaceutical ingredient is selected from the group consisting of phosphodiesterase inhibitors, preferably phosphodiesterase II I inhibitors or phosphodiesterase V inhibitors; non-thiazide sulphonamides; sulfonylurea derivatives; and hydroxy-1 ,4-naphthoquinone derivatives; or wherein the weight ratio 99:1 w/w to 4:1 w/w if a hyperbranched polyesteramide, preferably a hyperbranched polyesteramide having tertiary amine end groups or having hydroxyl end groups is used as the hyperbranched polymer, and c) a hydrophilic or hydrophobic carrier, preferably a hydrophilic carrier, more preferably the carrier is crystalline.
  • the hyperbranched polymer and the at least one pharmaceutical ingredient form a solid dispersion.
  • the powder or granulate can be prepared by using mixing, high shear mixing, and/or spray drying, fluid bed granulation or freeze drying. Preferably it is prepared by using high shear mixing, and/or spray drying or fluid bed granulation.
  • the preferred hyperbranched polymers, preferred APIs, preferred carriers, and preferred weight ratios of hyperbranched polymers/API etc. are described above.
  • compositions, powders and granulates are suitable for preparing a medicament.
  • the present invention also relates to a pharmaceutical dosage form comprising the pharmaceutical composition, powder or granulates according to any one of the preceding items, wherein preferably the pharmaceutical dosage form is a solid dosage form, preferably in the form of a pellet, a tablet, a capsule, a sachet, preferably the dosage form is a tablet.
  • the tablet can have one layer or can be a double or a multilayer tablet, which is preferably a film coated, or mantle coated tablet.
  • the pharmaceutical composition, powder or granulate and pharmaceutical dosage form does not contain a surfactant.
  • the present invention also refers to processes for preparing the inventive pharmaceutical compositions, powders, granulates and pharmaceutical dosage forms.
  • the processes according to the invention can be carried out using the specific hyperbranched polymers, APIs, carriers, preferred weight ratios of hyperbranched polymers/API etc. as described above.
  • the process according to the invention in a first step comprises the addition of the at least one hyperbranched polymer and the at least one active pharmaceutical ingredient to an organic solvent.
  • the obtained solution or dispersion is mixed.
  • an at least one carrier is added.
  • the solvent is removed.
  • the carrier can be alternatively combined with both constituents only after the solvent is removed or while it is being removed.
  • the removal of the solvent can be carried out by using standard techniques. Preferably techniques are applied that sufficiently remove the solvent already at the relatively low temperatures.
  • the step of removing the solvent is preferably accomplished at the temperatures of up to 60 °C, more preferably of up to 50 °C. This further enhances the stability of the composition .
  • the pharmaceutically active ingredient(s) can solidify and can, at least partially, but preferably completely also form a solid solution with the hyperbranched polymer.
  • the process of solvent removal allows the constituents to become amorphous, which also assists in increasing solubility, especially when performed in relative short periods of time by suitable techniques such as spray-drying, fluid-bed granulation or freeze drying, preferably spray-drying or fluid-bed granulation.
  • the process according the invention further comprises a drying step to remove residual water and organic solvents.
  • the temperature used in the drying process is preferably kept below 60°C, preferably below 50°C.
  • the drying can be carried out in a vacuum oven at a temperature of below 60°C, preferably below 50°C, most preferably at 40°C or below.
  • the at least one hyperbranched polymer and the at least one active pharmaceutical ingredient is completely dissolved in the organ ic solvent.
  • the carrier can be either combined with the hyperbranched polymer and the API before the solvent is removed or after solvent removal.
  • Another possibility is to spray the solution or dispersion of the at least one hyperbranched polymer and the at least one API onto the carrier as described below. In the latter case the combining of the carrier and the API/hyperbranched polymer and the solvent removal takes place in the same step.
  • remove the solvent in step c) by using high shear mixing, spray drying, fluid bed granulation or freeze drying as described herein.
  • step c) a solid dispersion of the API/hyperbranched polymer on the carrier is obtained.
  • the solvent in step c) can also be removed by using mixing, high shear mixing, spray drying, fluid bed granulation, freeze drying or the like as described herein to provide a solid dispersion of the constituents.
  • the processes according to the invention can be used for preparing solid pharmaceutical dosage forms as well as gels or solutions.
  • the solvent is removed in order to provide the mixture, preferably solid dispersion as a solid, preferably as a powder or granulate.
  • the solid obtained after removal of the solvent can e.g. be redissolved in a pharmaceutically acceptable solvent or buffer solution.
  • the solvents suitable for preparing the pharmaceutical compositions can be any solvent that at least partially dissolves both constituents (API and hyperbranched polymer).
  • the organic solvent is selected from the group consisting of C 2 -C 4 alkanols, such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol; aliphatic or alicyclic ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofurane; ketone, such as acetone, methyl ethyl ketone; dimethylsulphoxide and dimethylformamide; or mixtures thereof.
  • the constituents in the solvent can be optionally mixed.
  • At least 50 % w/w of both constituents get dissolved in the solvent, preferably more than 80 % w/w, more preferably over 90 % w/w, yet more preferably get completely dissolved in the solvent.
  • One process for preparing a pharmaceutical composition according to the invention comprises the steps of:
  • the process for preparing a powder or granulate according to the invention comprises the steps of:
  • step b) or step c) removing the solvent, wherein step b) or step c) further comprises combining the mixture with a hydrophilic or hydrophobic carrier, preferably a hydrophilic carrier, more preferably a crystalline carrier, even more preferably a carrier as defined above.
  • a hydrophilic or hydrophobic carrier preferably a hydrophilic carrier, more preferably a crystalline carrier, even more preferably a carrier as defined above.
  • the process according to the invention is particularly advantageous in terms of process yield and better end solubility when the at least one active pharmaceutical ingredient and the hyperbranched polymer is dissolved in the solvent.
  • the active pharmaceutical ingredient is obtained in amorphous form, being in contact with the hyperbranched polymer over a large surface area and extensively interacting with the polymer.
  • a solid dispersion is obtained.
  • step b) When preparing a powder or granulate, in step b) a hydrophilic or hydrophobic carrier, preferably hydrophilic carrier, more preferably a carrier as defined above, is added.
  • the carrier is in the form of particles, it is preferred that step b) is performed by depositing the hyperbranched polymer and active pharmaceutical ingredient on the surface of the carrier particles.
  • the constituents get deposited on the carrier preferably by applying techniques like high shear mixing, spray drying or fluid bed granulation, or the like.
  • the constituents are preferably still at least partly dissolved in the solvent when they reach the carrier and the solvent spreads over the carrier before being completely removed.
  • the parameters selected for the spray drying technique can, in principle, cause the solvent to evaporate before the constituents hit the carrier particles. Such conditions are less preferred. These techniques usually comprise to remove at least some of the solvent. However, a further step for solvent removal might be necessary.
  • the step of depositing the at least one pharmaceutically active ingredient and the at least one hyperbranched polymer can also be performed by simply mixing the components in the organic solvent and removing the solvent, wherein the solvent removal is also preferably carried out under mixing.
  • the additional pharmaceutically active ingredient can be added during the preparation of the solid dispersion of hyperbranched polymer, pharmaceutically active ingredient and carriers.
  • the additional pharmaceutically active ingredient can also be added after the solid dispersion has been prepared.
  • the additional pharmaceutically active ingredient can be added to the coating of a tablet or can be mixed with the powder or granulate containing the solid dispersion according to the invention.
  • a powder or granulate for the preparation of a pharmaceutical dosage form, e.g. a tablet or capsule, it is preferred to compress the powder or granulate into a tablet, or fill the powder or granulate into a capsule.
  • the preparation of a solid dosage form can be carried out by direct compression of the pharmaceutical composition, powder or granulate as described herein and optional further excipients obtained in process step c) into tablets.
  • the pharmaceutical composition, powder or granulate as described herein and optional further excipients can also be firstly granulated and then compressed in a tablet press to obtain tablets. Double- or multilayer- mode can be used on the tablet press to prepare double- or multi-layered tablets.
  • a tablet press can be used to obtain mantle coating.
  • the tablet is further mantle coated or film coated.
  • Film coating can be prepared by dissolving or dispersing suitable polymer for coating and if necessary plasticizers, stabilizers (antioxidants, acidic or basic agents, etc.) or the like in a vehicle and depositing the vehicle on the dosage form.
  • the process can be done for example by spraying technique or dip coating.
  • Example of a suitable apparatus to be used is a coating pan.
  • Mantle coating can be achieved by compacting the pharmaceutical formulation around the dosage form.
  • the pharmaceutical composition according to the present invention optionally being first transformed to the powder or the granulate, can be filled in the gelatine or hypromellose capsules.
  • various spheronization or extrusion techniques can be employed to prepare pellets. Pellets and capsules may be further coated.
  • the process of drying the pharmaceutical composition, powder, granulate or pharmaceutical dosage form further enhances the stability and handling properties.
  • the drying process can be applied at any step in the preparation of the composition, powder, granulate, tablet, pellet, capsule, or the like.
  • the present invention refers to the use of a crystalline carrier for the preparation of a pharmaceutical composition comprising hyperbranched polymer and a pharmaceutically active ingredient.
  • the use of crystalline carriers in the inventive pharmaceutical compositions provides advantageous properties.
  • the present invention also refers to the use of polyesteramide hyperbranched polymers for the preparation of a pharmaceutical composition comprising at least one active pharmaceutical ingredient, wherein the weight ratio of the hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 4:1 w/w.
  • Further preferred polyesteramide hyperbranched polymers, APIs, weight ratios of hyperbranched polymer/API, etc., which can be used are described above.
  • the present invention relates to the use of a hydrophilic or hydrophobic carrier for the preparation of a pharmaceutical composition
  • a hydrophilic or hydrophobic carrier for the preparation of a pharmaceutical composition
  • an active pharmaceutical ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives, preferably a non-thiazide sulphonamide, particularly preferred indapamide, in mixture with at least one hyperbranched polymer.
  • Preferred hydrophilic carriers and preferred non-thiazide sulphonamides and further ingredients, weight ratios, etc. are described above.
  • the present invention relates to the use of a hydrophilic carrier for the preparation of a pharmaceutical composition as defined above.
  • the present invention also relates to the use of an active pharmaceutical ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives for the preparation of a pharmaceutical composition comprising at least one hyperbranched polymer, wherein the at least one pharmaceutically active ingredient exhibits a solubility in an aqueous media at pH 6.8 and 37° C of less than 1 mg/ml, and wherein the weight ratio of the at least one hyperbranched polymer to the at least one active pharmaceutical ingredient is 99:1 w/w to 4: 1 w/w.
  • an active pharmaceutical ingredient selected from the group consisting of phosphodiesterase inhibitors, non-thiazide sulphonamides, sulfonylurea derivatives, and hydroxy-1 ,4-naphthoquinone derivatives
  • the pharmaceutical ingredient is selected from the group consisting of pimobendan, tadalfil, indapamide, glimepiride, and atovaquone.
  • Preferred hyperbranched polymers, APIs, weight ratios of hyperbranched polymer/API, etc., which can be used are described above.
  • Fig. 1A shows the effect of surface active ingredients or inactive ingredients on the solubility of glimepiride.
  • Fig 1 B shows the effect of linear polymers and amorphous form of glimepiride on the solubility of glimepiride.
  • Fig. 2 shows effects of hyperbranched polymers on the solubility of glimepiride.
  • Fig.3A shows a comparative dissolution study of glimepiride in phosphate buffer with pH 6.8 for samples containing Hybrane ® S1200 (examples 9-13).
  • Fig. 3B shows a comparative dissolution study of glimepiride in phosphate buffer with pH 6.8 for samples containing Hybrane ® S1200 (examples 14 - 16)
  • Fig.4 shows a comparative dissolution study of glimepiride in phosphate buffer with pH 6.8 for samples containing Hybrane ® HA1690 (examples 17-19).
  • Fig. 5 shows a comparative dissolution study of indapamide in phosphate buffer with pH 6.8 for samples containing Hybrane ® S1200.
  • Fig. 6 shows a comparative dissolution study of indapamide in phosphate buffer with pH 6.8 for samples containing Hybrane ® HA1690.
  • Fig. 7 shows a comparative dissolution study of pimobendan in phosphate buffer with pH 6.8 for samples containing Hybrane ® S1200.
  • Fig. 8 shows hygroscopicity of the pharmaceutical compositions comprising only hyperbranched polymer and an active pharmaceutical ingredient in comparison with the compositions further comprising a carrier.
  • Fig. 9 shows scanning electron microscope images of pharmaceutical composition particles, their size, shape, and growth.
  • Fig. 10 shows hygroscopicity of a pharmaceutical dosage form comprising only hyperbranched polymer and an active pharmaceutical ingredient in comparison with the dosage form further comprising a carrier.
  • Fig. 1 1 shows hygroscopicity of a pharmaceutical composition comprising hyperbranched polymer and a pharmaceutically active ingredient alone, comprising a hyperbranched polymer, pharmaceutically active ingredient and a crystalline carrier (lactose 200 Mesh) and comprising a hyperbranched polymer, pharmaceutically active ingredient and an amorphous carrier (spray dried lactose), respectively.
  • Fig. 12 shows ATR spectra of glimepiride and Hybrane HA1690 (upper and middle spectrum, respectively). Bottom spectrum presents the difference spectrum obtained by subtraction, the changes due to H-bond formation between glimepiride and hyperbranched polymer are marked with arrows.
  • Fig. 13A shows X-ray powder diffraction patterns of original glimepiride substance (bottom curve) and solid dispersions of glimepiride with PEG 6000 (middle curve) or Gelucire 50/13 (upper curve) in weight ratio of 5/95 % w/w.
  • Fig. 13B shows X-ray powder diffraction patterns of solid dispersions containing glimepiride and hyperbranched polymer Hybrane S1200 in weight ratio of 2/98 (A), 5/95 (B) and 20/80 (C), w/w and pure hyperbranched polymer Hybrane S1200 (D)
  • Fig. 13C shows X-ray powder diffraction patterns of solid dispersions containing glimepiride and hyperbranched polymer Hybrane S1200 in weight ratios of 7/93 (A), 10/90 (B), and 12/88 (C).
  • Comparative Example 1 Simple mixture of glimepiride and Texapon (sodium lauryl sulfate) - 9 % w/w
  • Comparative Example 2 Simple mixture of glimepiride and Polysorbate - 9 % w/w Comparative Example 3: Granulate comprising of milled glimepiride, Polysorbate and lactose (4/1/95 % w/w)
  • Comparative Example 4 Granulate comprising of unmilled glimepiride, Polysorbate and lactose (4/1/95 % w/w)
  • Glimepiride is currently marketed in a combination product with pioglitazone hydrochloride under the name Duetact (Takeda). Originator company has improved the low solubility by incorporation of a surfactant into a formulation (Polysorbate 80).
  • Comparative Example 6 Solid dispersions of glimepiride and linear polymer polyethylene glycol 6000 (PEG6000; average molar mass 6000 - 7500 g/mol) in weight ratio of 5/95 % w/w. Glimepiride and PEG6000 were dissolved in ethanol to obtain clear solution. The solution was stirred. The solvent was then removed at 40 °C in vacuum by evaporation. Dried solid dispersion was then manually milled into powder and sieved through a sieve with 250 ⁇ pores.
  • PEG6000 linear polymer polyethylene glycol 6000
  • Comparative Example 8 Amorphous form of glimepiride prepared by dissolving glimepiride in ethanol and subsequently freeze drying it (Lio5P, 5Pascal, Italy).
  • Approximately 50 % of the active ingredient (4 mg) is dissolved after 60 minutes of testing at following conditions: 37 °C in the USP Dissolution Tester, Apparatus II (Paddle method) using 900 ml of phosphate buffer (pH 6.8) as the dissolution medium and at a rotation rate of 75 rpm.
  • hyperbranched polyesteramides obtained from DSM were used. Used were: Hybrane ® S1200 and Hybrane ® HA1690.
  • Hybrane ® HA 1 690 represents a polyesteramide, wherein the structural units are hexa hydro phthalicacid anhyhdride, diisopropanolamine and N,N-bis-(3- dimethylaminopropyl)amine, and wherein the average molecular weight is 1 .600.
  • the provision of said polymers is described in the following publications:
  • solubility of the API can be particularly increased if a hyperbranched polyesteramide having tertiary amine groups, preferably Hybrane® HA 1690, is used as the hyperbranched polymer.
  • Hybrane ® S 1200 was used. Examples 9 - 19 (see Fig. 3A, Fig. 3B and Fig. 4)
  • Glimepiride was intimately mixed with the hyperbranched polymers as follows: First a physical mixture was prepared and then glimepiride and the polymer were dissolved in the mutual solvent isopropyl alcohol at room temperature while stirring continuously (100 rpm) with magnetic stirrer for 1 hour. The solution prepared was transparent. Then the solvent was removed (so called solvent method). I n cases where semi-solid or liquid product was obtained, granulation procedure was used. Polymer and the drug (i.e. API) were dissolved in a mutual solvent and then the solution was applied onto the crystalline lactose particles. The solution was applied in a fine spray onto the inert crystalline particles of lactose in the mortar and the forming mixture was mixed to ensure homogeneity.
  • solvent method solvent method
  • the moist mass was then d ried in a vacuum oven.
  • the temperature needed to assure evaporation of isopropyl alcohol was 40 °C.
  • After 3 days the samples were removed form the vacuum oven and a solid end product was obtained which was then manually milled to powder and sieved through a sieve with 250 ⁇ pores. The process was repeated for preparing compositions of various polymer/active ingredient weight ratios.
  • composition of the samples is presented in the table below.
  • Hyperbranched polymer Hybrane ® S1200, Hybrane ® HA1690
  • Example 1 1 5 95 / Example 12 5 95 400
  • Dissolution of glimepiride was assessed at 37 °C by the USP Dissolution Tester, Apparatus II (Paddle method) at a rotation rate of 75 rpm using 900 ml of phosphate buffer (pH 6.8) as dissolution medium.
  • the tested samples were added directly to the buffer in the correct amount to achieve a final concentration of 4,4 ⁇ g / mL glimepiride (equals therapeutic dose dissolved in 900 mL).
  • Aliquots, each of 2 ml, from the dissolution medium were withdrawn at time intervals of 5, 15, 30, 60 minutes. The samples were withdrawn through syringe and filtered through Millipore filter and analyzed for glimepiride content using HPLC method.
  • the amount of dissolved glimepiride was estimated by reversed-phase HPLC (Waters Alliance) in a binary mode, with a photodiode array detector and a communication bus module.
  • the retention time of the drug was approximately 4 min.
  • the loading capacity of glimepiride complexed with particular HB polymer in solid dispersions was determined (see table below).
  • the maximum loading capacity of glimepiride for both Hybrane S1200 or Hybrane HA1690 polymers is around 5 % w/w, meaning that HB polymers of different chemical composition, i.e., Hybrane S1200 or Hybrane HA1690 do not show any significant differences.
  • Solid dispersions containing more than 2 %, preferably between 2 % w/w and 12 % w/w, more preferably between 2 % w/w and 10% w/w, and up to 20 % w/w of API show improved loading capabilities.
  • indapamide The samples of indapamide were prepared as in examples 9 to 16. Dissolution of indapamide was assessed at 37 °C by the USP Dissolution Tester, Apparatus II (Paddle method), using 900 ml of phosphate buffer (pH 6.8) as the dissolution medium and at a rotation rate of 75 rpm. The tested samples were added directly to buffer in an amount in order to achieve a final concentration of 15 ⁇ g / mL indapamide. Aliquots, each of 2 ml, from the dissolution medium were withdrawn at time intervals of 5, 15, 30, 60 minutes. The samples were withdrawn through syringe and filtered through Millipore filter in order to separate the undissolved sample and analyzed for indapamide using UV spectrofotometry at 287 nm.
  • polyesteramide hyperbranched polymers remarkably enhance the solubility of the indapamide.
  • the samples of pimobendan were prepared as in examples 9 to 16. Dissolution of pimobendan was assessed at 37 °C by the USP Dissolution Tester, Apparatus I I (Paddle method) at a rotation rate of 75 rpm, using 900 ml of phosphate buffer (pH 6.8) as the dissolution medium. The tested samples were added directly to the buffer in the correct amount to achieve a final concentration of 5.5 ⁇ g / mL pimobendan (equals therapeutic dose dissolved in 900 mL). Aliquots, each of 2 ml, from the dissolution medium were withdrawn at time intervals of 5, 15, 30, 60 minutes. The samples were withdrawn through syringe and filtered through Millipore filter in order to separate the undissolved sample and analyzed for pimobendan using HPLC method.
  • polyesteramide Hybrane ® S1200 when admixed with pimobendan (2% and 5% of pharmaceutically active ingredient) significantly increases the solubility of the active ingredient.
  • the combination of an active ingredient and hyperbranched polymer was evaluated for the effect it has on the solubility of the following compounds: tadalafil, atovaquone, indapamide.
  • the samples were prepared according to the process described in example 9 and exhibited an increase in the solubility of the respective active ingredient. The increase was 55-fold, 100-fold and 140-fold, respectively.
  • Samples as in example 23 that contained only the hyperbranched polymer and the active pharmaceutical ingredient were compressed into approximately 100 mg tablets and the ones that contained also the hydrophilic carrier lactose (samples of the composition as presented in example 12) were compressed into approximately 500 mg tablets by using hydraulic press with force of 10000 N.
  • the HPLC analysis were performed with a Waters system equipped with a C18, 5 ⁇ , 150 X 4.6 mm column which was maintained in a column oven at 30 °C.
  • the flow rate was 1 mL/min, and the detection wavelength was 228 nm. All impurities eluted within 15 minutes represent the total amount of glimepiride impurities.
  • the infrared spectra were recorded on a Perkin Elmer System 2000 spectrometer. Typically 256 scans were averaged and apodized with triangular functions at nominal resolution of 2 cm "1 . Spectra were measured at room temperature in ATR and transmission mode, in the latter case in the form of pressed KBr pellets. ATR spectra were recorded on a Specac Golden Gate ATR cell equipped with a diamond crystal. ATR spectra were used without additional processing such as corrections due to frequency dependent depth of penetration or spectral anomalies due to reflection.
  • ATR spectrum possesses besides the absorption information also the features due to reflection.
  • the influence of the so called anomalous dispersion may significantly disturb the band shape and band frequency. These disturbances depend on the ratio between the refractive indices of bearing crystal and sample as well as angle of incidence. Less intensive bands are less affected by anomalous dispersion, which is evidenced by comparing the band frequencies retrieved from transmission and ATR spectra (see table below).
  • the ATR spectra of glimepiride and Hybrane HA1690 are presented in Figure 12 (upper and middle spectrum, respectively).
  • the ATR spectra of pure hyperbranched polymers were subtracted from the spectra of solid dispersions containing glimepiride and hyperbranched polymer in weight ratio of 5/95 % w/w.
  • the difference spectrum for Hybrane HA1690 is presented in Figure 12 (bottom spectrum).
  • X-ray patterns were obtained using X'Pert PRO MPD powder diffracto meter. Samples were exposed to CuKa radiation in the range 2° ⁇ 2 ⁇ > 40°. The integration time per step was 50 seconds. XRD analysis was performed to analyze polymorph modifications of glimepiride within the solid dispersions.
  • X-ray diffractogram ( Figure 13A, bottom curve) of the original glimepiride shows its crystalline form as demonstrated by sharp and intense peaks.
  • the characteristic peaks of glimepiride are also present in solid dispersions with PEG 6000 or Gelucire 50/13 ( Figure 13A, middle and upper curve, respectively) showing that glimepiride is preserved in the same crystalline form within solid dispersions with general linear polymers (i.e. PEG 6000 or Gelucire 50/13).
  • PEG 6000 or Gelucire 50/13 general linear polymers

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Abstract

La présente invention appartient au domaine de l'industrie pharmaceutique et porte sur une composition pharmaceutique comprenant au moins un polymère hyper-ramifié et au moins un principe pharmaceutiquement actif, le polymère et le principe pharmaceutiquement actif étant présents dans un rapport en poids spécifique, et sur un procédé pour la préparation de ladite composition pharmaceutique. La présente invention porte également sur une poudre ou des granulés comprenant au moins un polymère hyper-ramifié et au moins un ingrédient pharmaceutiquement actif dans un rapport en poids spécifique, sur un procédé de préparation de ladite poudre ou desdits granulés, et sur une forme posologique pharmaceutique comprenant la composition pharmaceutique, la poudre ou les granulés. De plus, la présente invention porte sur un procédé de préparation d'une dispersion solide d'un polymère hyper-ramifié et au moins un principe actif (API). En outre, l'invention concerne l'utilisation d'un support cristallin pour la préparation du mélange de polymère hyper-ramifié et de principe pharmaceutiquement actif, ainsi que sur l'utilisation de polymères hyper-ramifiés polyesteramides pour la préparation d'une composition pharmaceutique, sur l'utilisation d'un support hydrophile ou hydrophobe pour la préparation de ladite composition comprenant un groupe spécifique d'API, et sur l'utilisation d'un API spécifique et d'au moins un polymère hyper-ramifié pour la composition d'une préparation pharmaceutique.
EP10771053A 2009-10-07 2010-10-06 Composition pharmaceutique comprenant un principe actif peu soluble et un polymère hyper-ramifié Withdrawn EP2485716A2 (fr)

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US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
EP1579862A1 (fr) 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Utilisation des inhibiteurs de PDE III pour la réduction de la taille du coeur chez des mammifères souffrant d'insufficances cardiaques
EP1920785A1 (fr) 2006-11-07 2008-05-14 Boehringer Ingelheim Vetmedica Gmbh Préparation liquide contenant un complexe du pimobendane et de la cyclodextrine
WO2013135852A1 (fr) 2012-03-15 2013-09-19 Boehringer Ingelheim Vetmedica Gmbh Formulation pharmaceutique de comprimé pour le secteur médical vétérinaire, son procédé de production et utilisation
WO2014003678A1 (fr) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Compositions pharmaceutiques comprenant de l'ambrisentan et des particules de dispersion solide contenant du tadalafil
WO2014003677A1 (fr) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil
WO2014045307A2 (fr) 2012-09-20 2014-03-27 Ipca Laboratories Limited Composition pharmaceutique
AU2014292086B2 (en) 2013-07-19 2019-08-08 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
WO2015082389A1 (fr) 2013-12-04 2015-06-11 Boehringer Ingelheim Vetmedica Gmbh Compositions pharmaceutiques améliorées de pimobendan
WO2017041679A1 (fr) * 2015-09-07 2017-03-16 常州方楠医药技术有限公司 Dispersion solide de tadalafil et d'excipients pharmaceutiques, et procédé de préparation de la dispersion solide
CN105613547B (zh) * 2016-03-30 2017-10-24 青岛农业大学 格列本脲在制备用于防治由植物病原菌引起的植物病害的杀菌剂中的用途
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
CN112535665A (zh) * 2020-12-14 2021-03-23 宁夏医科大学 一种格列吡嗪固体分散体及制备方法和包含其的格列吡嗪固体分散体片及制备方法
US20240197727A1 (en) 2022-12-15 2024-06-20 Boehringer Ingelheim Vetmedica Gmbh Solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers

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