CA2388614A1 - Pharmaceutical agent preparations - Google Patents
Pharmaceutical agent preparations Download PDFInfo
- Publication number
- CA2388614A1 CA2388614A1 CA002388614A CA2388614A CA2388614A1 CA 2388614 A1 CA2388614 A1 CA 2388614A1 CA 002388614 A CA002388614 A CA 002388614A CA 2388614 A CA2388614 A CA 2388614A CA 2388614 A1 CA2388614 A1 CA 2388614A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- component
- dosage form
- weight
- solid dosage
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Abstract
The invention relates to solid pharmaceutical galenic forms comprising an agent in the form of a physical mixture of two different preparations with regard to the physical state of the agent.
Description
PHARMACEUTICAL AGENT PREPARATIONS
The present invention relates to solid dosage forms of an active pharmaceutical ingredient in which a physical mixture of at least two preparations of the active ingredient which differ in relation to the physical state of the active ingredient is present. The invention further relates to dosage forms which, comprise a third preparation differing in relation to the physical state of the active ingredient.
Great problems concerning the bioavailability of dosage forms arise with a whole, series of very effective active pharmaceutical ingredients, especially when uniform blood plasma concentrations are wanted, but.excessively high blood plasma levels must be avoided, because of the severe side effects, during long-term therapy. This applies for example to many immunosuppressants, HIV
therapeutic agents or CNS-active substances.
Cyclosporines, a series of nonpolar, cyclic oligopeptides, are distinguished by their immunosuppressant effect. Of them, cyclosporine A in particular has attained therapeutic significance, consists of 11 amino acids and is obtained by fermentation.
Although cyclosporine formulations have been developed both for oral and for intravenous use, it is preferred to administer cyclosporine orally because it ensures better patient compliance.
However, cyclosporine A is quite large, with a molecular weight of 1202 g/mol, and is very lipophilic, which is also manifested by a very low solubility in water (<0.004% m/V). Owing to a certain solubility in oils such as olive oil, and in ethanol, it has been possible to develop emulsion concentrates which on oral administration lead to a bioavailability of about 30$, although this is relatively variable (cf. R.H. Miiller et al. in "Pharmazeutische Technologies Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, pp.
118-125).
Oral forms currently available on the market are accordingly either emulsion concentrates for administration as solutions or microemulsions used to fill capsules. In both cases, solvents such as ethanol and/or oil are employed to stabilize the cyclosporine.
w v However, the biolavailability may be subject to great variations in the range from 10 to 60$. These variations are connected with the pharmaceutical form and the state of the preparation in the gastrointestinal tract. In addition, the natural digestion of fats has a significant influence on the absorption of cyclosporine administered orally.
WO 97/07787 also describes cyclosporine formulations which, beside the active ingredient, comprise an alkanolic solvent such as ethanol or propylene glycol, and a nonionic polyoxyalkylene derivative as surface-active substance.
However, such forms have the disadvantage firstly that they contain solvents, especially ethanol, and secondly that the cyclosporine tends to recrystallize at low temperatures, which is a problem in relation to storage stability. This is because such precipitates are very substantially unabsorbed so that a uniform bioavailability is not ensured in some circumstances.
EP-A 425 892 discloses a method for improving the bioavailability of active pharmaceutical ingredients with peptide bonds, wherein a solution of the active ingredient in a water-miscible organic solvent is rapidly mixed with an aqueous colloid so that the active ingredient precipitates in colloidal form.
WO 93/10767 describes oral administration forms for pharmaceutical peptides in which the pharmaceutical is incorporated into a gelatin matrix in such a way that the colloidal particles which form have a neutral charge. However, the disadvantage of such forms is their tendency to flocculation.
It is also known, for example, from EP-A 240 904, that molecular dispersions of an active ingredient in a polymer matrix can be obtained by melt extrusion.
It is an object of the present invention to find dosage forms suitable for oral administration of active ingredients of low bioavailability, such as, for example, cyclosporine, which contain no solvents and are comparable in their bioavailability to microemulsions.
We have found that this object is achieved by the dosage forms defined at the outset, in which the active ingredient is present in the form of a physical mixture of at least two preparations of the active ingredient which differ in relation to the physical state of the active ingredient. Pharmaceutical forms in which a w i third physically different form of the active ingredient is additionally present have also been found.
According to the invention, the active ingredient is present in a first preparation (component 1) in the form of solid, X-ray amorphous particles colloidally dispersed in a matrix of a polymeric coating material. In a second preparation (component 2), the active ingredient is present as a molecular dispersion in an excipient matrix. In a third, physically different form (component 3), the active ingredient is present in the form of crystalline particles.
.The dosage form according to the invention is suitable in principle for all active ingredients of low solubility in water and low bioavailability, but especially for cyclosporine.
It is possible according to the invention to process all cyclosporines, but cyclosporine A is preferred. Cyclosporine A
has a melting point of 148 to 151~C and is employed as a colorless crystalline substance.
In component 1, the active ingredient is colloidally embedded in the form of X-ray amorphous particles in a coating matrix consisting of one or more polymeric stabilizers. Suitable polymeric stabilizers are swellable protective colloids such as, for example, bovine, porcine or fish gelatin, starch, dextrin, pectin, gum arabic, ligninsulfonates, chitosan, polystyrenesulfonate, alginates,' caseine, caseinate, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, milk powder, dextran, whole milk or skimmed milk or mixtures of these protective colloids. Also suitable are homo- and copolymers based on the following monomers: ethylene oxide, propylene oxide, acrylic acid, malefic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, a- and ~i-aspartic acid. One of said gelatin types is particularly preferably employed, in particular acid- or base-degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, H 100 and B 200, and low molecular weight, enzymatically degraded gelatin types with Bloom number 0 and molecular weights of from 15,000 to 25,000 D, such as, for example, Collagel A and Gelitasol P (from Stoess, Eberbach), and mixtures of these gelatin types.
These preparations additionally comprise low molecular weight surface-active compounds. Particularly suitable as such are amphiphilic compounds or mixtures of such compounds. Suitable in principle are all surfactants with an HLB of from 5 to 20.
The present invention relates to solid dosage forms of an active pharmaceutical ingredient in which a physical mixture of at least two preparations of the active ingredient which differ in relation to the physical state of the active ingredient is present. The invention further relates to dosage forms which, comprise a third preparation differing in relation to the physical state of the active ingredient.
Great problems concerning the bioavailability of dosage forms arise with a whole, series of very effective active pharmaceutical ingredients, especially when uniform blood plasma concentrations are wanted, but.excessively high blood plasma levels must be avoided, because of the severe side effects, during long-term therapy. This applies for example to many immunosuppressants, HIV
therapeutic agents or CNS-active substances.
Cyclosporines, a series of nonpolar, cyclic oligopeptides, are distinguished by their immunosuppressant effect. Of them, cyclosporine A in particular has attained therapeutic significance, consists of 11 amino acids and is obtained by fermentation.
Although cyclosporine formulations have been developed both for oral and for intravenous use, it is preferred to administer cyclosporine orally because it ensures better patient compliance.
However, cyclosporine A is quite large, with a molecular weight of 1202 g/mol, and is very lipophilic, which is also manifested by a very low solubility in water (<0.004% m/V). Owing to a certain solubility in oils such as olive oil, and in ethanol, it has been possible to develop emulsion concentrates which on oral administration lead to a bioavailability of about 30$, although this is relatively variable (cf. R.H. Miiller et al. in "Pharmazeutische Technologies Moderne Arzneiformen", Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, pp.
118-125).
Oral forms currently available on the market are accordingly either emulsion concentrates for administration as solutions or microemulsions used to fill capsules. In both cases, solvents such as ethanol and/or oil are employed to stabilize the cyclosporine.
w v However, the biolavailability may be subject to great variations in the range from 10 to 60$. These variations are connected with the pharmaceutical form and the state of the preparation in the gastrointestinal tract. In addition, the natural digestion of fats has a significant influence on the absorption of cyclosporine administered orally.
WO 97/07787 also describes cyclosporine formulations which, beside the active ingredient, comprise an alkanolic solvent such as ethanol or propylene glycol, and a nonionic polyoxyalkylene derivative as surface-active substance.
However, such forms have the disadvantage firstly that they contain solvents, especially ethanol, and secondly that the cyclosporine tends to recrystallize at low temperatures, which is a problem in relation to storage stability. This is because such precipitates are very substantially unabsorbed so that a uniform bioavailability is not ensured in some circumstances.
EP-A 425 892 discloses a method for improving the bioavailability of active pharmaceutical ingredients with peptide bonds, wherein a solution of the active ingredient in a water-miscible organic solvent is rapidly mixed with an aqueous colloid so that the active ingredient precipitates in colloidal form.
WO 93/10767 describes oral administration forms for pharmaceutical peptides in which the pharmaceutical is incorporated into a gelatin matrix in such a way that the colloidal particles which form have a neutral charge. However, the disadvantage of such forms is their tendency to flocculation.
It is also known, for example, from EP-A 240 904, that molecular dispersions of an active ingredient in a polymer matrix can be obtained by melt extrusion.
It is an object of the present invention to find dosage forms suitable for oral administration of active ingredients of low bioavailability, such as, for example, cyclosporine, which contain no solvents and are comparable in their bioavailability to microemulsions.
We have found that this object is achieved by the dosage forms defined at the outset, in which the active ingredient is present in the form of a physical mixture of at least two preparations of the active ingredient which differ in relation to the physical state of the active ingredient. Pharmaceutical forms in which a w i third physically different form of the active ingredient is additionally present have also been found.
According to the invention, the active ingredient is present in a first preparation (component 1) in the form of solid, X-ray amorphous particles colloidally dispersed in a matrix of a polymeric coating material. In a second preparation (component 2), the active ingredient is present as a molecular dispersion in an excipient matrix. In a third, physically different form (component 3), the active ingredient is present in the form of crystalline particles.
.The dosage form according to the invention is suitable in principle for all active ingredients of low solubility in water and low bioavailability, but especially for cyclosporine.
It is possible according to the invention to process all cyclosporines, but cyclosporine A is preferred. Cyclosporine A
has a melting point of 148 to 151~C and is employed as a colorless crystalline substance.
In component 1, the active ingredient is colloidally embedded in the form of X-ray amorphous particles in a coating matrix consisting of one or more polymeric stabilizers. Suitable polymeric stabilizers are swellable protective colloids such as, for example, bovine, porcine or fish gelatin, starch, dextrin, pectin, gum arabic, ligninsulfonates, chitosan, polystyrenesulfonate, alginates,' caseine, caseinate, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, milk powder, dextran, whole milk or skimmed milk or mixtures of these protective colloids. Also suitable are homo- and copolymers based on the following monomers: ethylene oxide, propylene oxide, acrylic acid, malefic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, a- and ~i-aspartic acid. One of said gelatin types is particularly preferably employed, in particular acid- or base-degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, H 100 and B 200, and low molecular weight, enzymatically degraded gelatin types with Bloom number 0 and molecular weights of from 15,000 to 25,000 D, such as, for example, Collagel A and Gelitasol P (from Stoess, Eberbach), and mixtures of these gelatin types.
These preparations additionally comprise low molecular weight surface-active compounds. Particularly suitable as such are amphiphilic compounds or mixtures of such compounds. Suitable in principle are all surfactants with an HLB of from 5 to 20.
Examples of suitable surface-active substances are: esters of long-chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their ethoxylation products, esters of fatty acid monoglycerides with acetic acid, citric acid, lactic acid or diacetyltartaric acid, polyglycerol fatty acid esters such as, for example, the monostearate of triglycerol, sorbitan fatty acid esters, propylene glycol fatty acid esters, 2-(2-stearoyllactyl)lactic acid salts and lecithin. Ascorbyl palmitate is preferably employed.
Id The amounts of the various components are chosen according to the invention so that the preparations comprise from 0.1 to 70~ by weight, preferably 1 to 40~ by weight, of active ingredient, from I to 80~ by weight, preferably 10 to 60$ by weight, of one or more polymeric stabilizers and from 0 to 50~ by weight, preferably 0.5 to 20$ by weight, of one or more low molecular weight stabilizers. The percentages by weight are based on a dry powder.
To produce the first formulation, firstly a solution of the active ingredient in a suitable solvent is prepared, solution meaning in this connection a true solution or a melt emulsion.
Suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, nitrogen and oxygen. They are expediently at least 10~ by weight miscible with water and have a boiling point below 200~C and/or have fewer than 10 carbon atoms. Corresponding alcohols, esters, ketones and acetals are preferred. In particular, ethanol, n-propanol, isopropanol, 1,2-butanediol 1-methyl ether, 1,2-propanediol 1-n-propyl ether or acetone is used.
In one embodiment of the invention, a solution of the active ingredient is prepared by dissolving the latter in the chosen solvent at temperatures in the range preferably of from 20 to 150°C, within a period of less than 120 seconds, it being possible where appropriate to operate under a gage pressure of up to 100 bar, preferably 30 bar.
In a further preferred embodiment, the active ingredient solution is prepared by heating the mixture of active ingredient and solvent within a period of less than 10 seconds above the melting point of the active ingredient to 150 to 240~G, it being possible where appropriate to operate under a gage pressure of up to 100 bar, preferably 30 bar.
The concentration of the active ingredient solution prepared in this way is generally from 10 to 500 g of active ingredient per 1 kg of solvent. In a preferred embodiment of the process, the low molecular weight stabilizer is added directly to the active 5 ingredient solution.
In a process step which follows this, the active ingredient solution is mixed with an aqueous solution of the polymeric coating material. The concentration of the solution of the polymeric coating material is from 0.1 to 200 g/1, preferably 1 to 100 g/1.
In order to obtain particle sizes as small as possible in the mixing step, it is advisable for the mechanical energy input to be high when mixing the active ingredient solution with the solution of the coating material. Such an energy_input can take place, for example, by vigorous stirring or shaking in a suitable apparatus, or by injecting the two components as a powerful jet into a mixing chamber so that vigorous mixing occurs.
The mixing step can be carried out discontinuously or, preferably, continuously. The mixing step results in the active ingredient being precipitated in the form of solid, X-ray amorphous particles. The colloidal suspension obtained in this way can be converted in a manner known per se into a dry powder, for example by spray drying, freeze drying or fluidized-bed drying.
The procedure for producing the preparations according to the invention is to adjust the pH of the solution of the coating material, in particular of gelatin, and of a solution of the active ingredient so that the active ingredient particles which are forming do not develop a neutral charge, i.e. the pH of the gelatin solution must not be adjusted to a value such that a stage of neutral charge is set up when the particles form. The particles are preferably produced at pH values above 7.
The average diameter of the solid active ingredient particles in the matrix of the polymeric coating material is from 20 to 1000 nm, preferably 100 to 600 nm. The spherical active ingredient particles are completely X-ray amorphous. X-ray amorphous means in this connection the absence of crystal interferences in X-ray powder diagrams (cf. H.P. Klug, L.E.
Alexander, "X-Ray Diffraction procedures for Polycrystalline and Amorphous Materials", John Wiley, New York, 1959). The active ingredient particles are distinguished by having a negative charge after redispersion in aqueous medium at a pH above 5.
In the second formulation, the active ingredient is in the form of a molecular dispersion in an excipient matrix. Such molecular dispersions of an active ingredient in a matrix are also referred to as "solid solutions" (cf. Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300). Such solid solutions can be produced by the solution process by dissolving the active ingredient together with the components forming the excipient matrix in a suitable solvent, and then removing the solvent. Examples of suitable solvents are water, ethanol, isopropanol, acetone, chlorinated hydrocarbons such as methylene chloride or chloroform, tetrahydrofuran, toluene or methyl ethyl ketone. The solvent is normally evaporated off in vacuo.
Such solid solutions can also be produced by the melt process where the active ingredient and the starting materials forming the excipient matrix are intimately mixed while molten. The process is preferably carried out without addition of solvents.
The melt process is carried out in a kneader or screw extruder.
Examples of suitable kneaders are those supplied by Haake or Farrell.
The melt is preferably produced in a screw extruder, particularly preferably a twin screw extruder with and without kneading disks or similar mixing elements. Co-rotating twin screw extruders are particularly preferred.
Depending on the composition, processing generally takes place at temperatures of from 40 to 260~C, preferably 50 to 200~C.
The starting materials can be fed into the extruder or kneader singly or as premix. Addition preferably takes place in the form of powdered or granulated premixes. Thus, the liquid or oily surface-active substance can be previously mixed with another starting material to give free-flowing granules. Addition of the surface-active substance in liquid form, for example via liquid pumps, which are preferably heated in the case of semisolid substances, is likewise possible.
It is also possible first to dissolve the active ingredient in the surface-active substance, and then to granulate this mixture with the polymer. In this case, the active ingredient itself must not melt.
Id The amounts of the various components are chosen according to the invention so that the preparations comprise from 0.1 to 70~ by weight, preferably 1 to 40~ by weight, of active ingredient, from I to 80~ by weight, preferably 10 to 60$ by weight, of one or more polymeric stabilizers and from 0 to 50~ by weight, preferably 0.5 to 20$ by weight, of one or more low molecular weight stabilizers. The percentages by weight are based on a dry powder.
To produce the first formulation, firstly a solution of the active ingredient in a suitable solvent is prepared, solution meaning in this connection a true solution or a melt emulsion.
Suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, nitrogen and oxygen. They are expediently at least 10~ by weight miscible with water and have a boiling point below 200~C and/or have fewer than 10 carbon atoms. Corresponding alcohols, esters, ketones and acetals are preferred. In particular, ethanol, n-propanol, isopropanol, 1,2-butanediol 1-methyl ether, 1,2-propanediol 1-n-propyl ether or acetone is used.
In one embodiment of the invention, a solution of the active ingredient is prepared by dissolving the latter in the chosen solvent at temperatures in the range preferably of from 20 to 150°C, within a period of less than 120 seconds, it being possible where appropriate to operate under a gage pressure of up to 100 bar, preferably 30 bar.
In a further preferred embodiment, the active ingredient solution is prepared by heating the mixture of active ingredient and solvent within a period of less than 10 seconds above the melting point of the active ingredient to 150 to 240~G, it being possible where appropriate to operate under a gage pressure of up to 100 bar, preferably 30 bar.
The concentration of the active ingredient solution prepared in this way is generally from 10 to 500 g of active ingredient per 1 kg of solvent. In a preferred embodiment of the process, the low molecular weight stabilizer is added directly to the active 5 ingredient solution.
In a process step which follows this, the active ingredient solution is mixed with an aqueous solution of the polymeric coating material. The concentration of the solution of the polymeric coating material is from 0.1 to 200 g/1, preferably 1 to 100 g/1.
In order to obtain particle sizes as small as possible in the mixing step, it is advisable for the mechanical energy input to be high when mixing the active ingredient solution with the solution of the coating material. Such an energy_input can take place, for example, by vigorous stirring or shaking in a suitable apparatus, or by injecting the two components as a powerful jet into a mixing chamber so that vigorous mixing occurs.
The mixing step can be carried out discontinuously or, preferably, continuously. The mixing step results in the active ingredient being precipitated in the form of solid, X-ray amorphous particles. The colloidal suspension obtained in this way can be converted in a manner known per se into a dry powder, for example by spray drying, freeze drying or fluidized-bed drying.
The procedure for producing the preparations according to the invention is to adjust the pH of the solution of the coating material, in particular of gelatin, and of a solution of the active ingredient so that the active ingredient particles which are forming do not develop a neutral charge, i.e. the pH of the gelatin solution must not be adjusted to a value such that a stage of neutral charge is set up when the particles form. The particles are preferably produced at pH values above 7.
The average diameter of the solid active ingredient particles in the matrix of the polymeric coating material is from 20 to 1000 nm, preferably 100 to 600 nm. The spherical active ingredient particles are completely X-ray amorphous. X-ray amorphous means in this connection the absence of crystal interferences in X-ray powder diagrams (cf. H.P. Klug, L.E.
Alexander, "X-Ray Diffraction procedures for Polycrystalline and Amorphous Materials", John Wiley, New York, 1959). The active ingredient particles are distinguished by having a negative charge after redispersion in aqueous medium at a pH above 5.
In the second formulation, the active ingredient is in the form of a molecular dispersion in an excipient matrix. Such molecular dispersions of an active ingredient in a matrix are also referred to as "solid solutions" (cf. Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300). Such solid solutions can be produced by the solution process by dissolving the active ingredient together with the components forming the excipient matrix in a suitable solvent, and then removing the solvent. Examples of suitable solvents are water, ethanol, isopropanol, acetone, chlorinated hydrocarbons such as methylene chloride or chloroform, tetrahydrofuran, toluene or methyl ethyl ketone. The solvent is normally evaporated off in vacuo.
Such solid solutions can also be produced by the melt process where the active ingredient and the starting materials forming the excipient matrix are intimately mixed while molten. The process is preferably carried out without addition of solvents.
The melt process is carried out in a kneader or screw extruder.
Examples of suitable kneaders are those supplied by Haake or Farrell.
The melt is preferably produced in a screw extruder, particularly preferably a twin screw extruder with and without kneading disks or similar mixing elements. Co-rotating twin screw extruders are particularly preferred.
Depending on the composition, processing generally takes place at temperatures of from 40 to 260~C, preferably 50 to 200~C.
The starting materials can be fed into the extruder or kneader singly or as premix. Addition preferably takes place in the form of powdered or granulated premixes. Thus, the liquid or oily surface-active substance can be previously mixed with another starting material to give free-flowing granules. Addition of the surface-active substance in liquid form, for example via liquid pumps, which are preferably heated in the case of semisolid substances, is likewise possible.
It is also possible first to dissolve the active ingredient in the surface-active substance, and then to granulate this mixture with the polymer. In this case, the active ingredient itself must not melt.
In the case of temperature-sensitive active ingredients it may also be advisable first to melt the other starting materials and only then to add the active ingredient.
The starting materials are accordingly processed together to give a melt which is processed to a homogeneous composition by input of mechanical energy, in particular in the form of shear forces.
The homogeneous melt is then extruded through a die or a breaker plate and shaped. This can take place by cutting off the extrudate by conventional techniques, for example with the aid of rotating knives or by compressed air cutting off, resulting in pellets or granules. It is further possible for the shaping to take place as described in EP-A 240 906, by the extrudate being passed between two counter-rotating calender rolls and being directly shaped to tablets. The melt can likewise be discharged through the open head and, after solidification, where appropriate also ground or further processed by suitable granulating equipment such as rolls or compacting units.
Examples of suitable matrix formers which the second formulations can contain are melt-processable water-soluble or water-swellable polymers. Water-soluble means that at least 1 g of the polymer dissolves in 10 ml of water at 25~C. Water-swellable means that the water uptake at 25~C and 75$ relative humidity is more than 1~
by weight, without the polymer dissolving.
Examples of suitable polymers are homo- and copolymers of N-vinylpyrrolidone with Fikentscher K values of from 19 to 100. A
suitable comonomer is, in particular, vinyl acetate, as is vinyl propionate, vinylcaprolactam or vinylimidazole.
Likewise suitable are cellulose derivatives, for example hydroxyalkylcelluloses such as hydroxypropylcellulose, alkylcelluloses or alkylhydroxyalkylcelluloses such as hydroxypropylmethylcelluloses.
Additionally suitable are polyethylene glycols with molecular weights of from 1500 to 10 million D or polyoxyethylene/polyoxypropylene block copolymers.
It is, of course, also possible to employ mixtures of said polymers.
Also suitable as matrix formers are sugar alcohols such as erythritol, isomalt, mannitol, sorbitol, xylitol or mixtures of such sugar alcohols.
The matrix may also contain pharmaceutically acceptable excipients such as bulking agents, lubricants, mold release agents, flow regulators, plasticizers, dyes, flavorings and/or stabilizers in the amounts customary for this purpose.
In a further embodiment of the invention, the active ingredient dosage forms may comprise a third formulation (component 3). The active ingredient is present in this formulation in the form of particles, the active ingredient in the particles having a crystallinity of at least 20$. The crystallinity refers to the proportion of active substance which is not in amorphous form.
The active ingredient can also be present in component 3 in different crystal modifications.
The active ingredient is present in this formulation in particular as pure crystalline substance without further excipients. The particles have average diameters in the range from 0.05 to 200 dun, preferably 0.1 to 50 Eun. The crystalline particles can be obtained from crude crystalline product by grinding processes known per se. Examples of suitable grinding processes are dry or wet grinding. Examples of suitable apparatus are ball mills, pinned disk mills or air jet mills.
The dosage forms according to the invention are obtained by physically mixing components 1, 2 and 3. The total amount of active ingredient in component 1 is preferably in the range from 10 to 70~ by weight, particularly preferably from 20 to 60$ by weight, in component 2 is preferably in the range from 10 to 70$
by weight, particularly preferably from 20 to 60~ by weight, and in component 3 is preferably in the range from 0 to 30~ by weight. The physical properties of the individual components are unchanged after the mixing.
The physical mixtures according to the invention of two or three preparations of the active ingredient in each of which the active ingredient is present in a different physical form can be employed in all oral drug forms suitable for this purpose. Thus, for example, they can be packed into hard or soft gelatin capsules or be compressed to tablets under conditions known per se.
Surprisingly, the dosage forms according to the invention have bioavailabilities which are higher than those of the individual components. Such a synergistic effect was unexpected for the skilled worker.
w The results of a study on dogs prove the good bioavailability of the dosage form by comparison with a product on the market.
Production Example 1 Production of an active ingredient dry powder with an active ingredient content in the region of 10~ by weight a) Production of the micronisate 3 g of cyclosporine A were stirred into a solution of 0.6 g of ascorbyl palmitate in 36 g of isopropanol at 25°C, resulting in a clear solution.
To precipitate the cyclosporine A in colloidal form, this solution was fed at 25°C into a mixing chamber. It was there mixed with 537 g of an aqueous solution of 14.4 g gelatin B
100 Hloom and 12.6 g of lactose in deionized water which has been adjusted to pH 9.2 with 1 N NaOH. The pressure throughout the process was limited to 30 bar. After mixing, a colloidal dispersion of cyclosporine A was obtained with a cloudy white appearance.
The average particle size was determined by quasielastic light scattering to be 256 nm with a variance of 31~.
Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.62 N,m with a fine content of the distribution of 99.2$ <1.22 ~.m.
b) Drying of dispersion a) to give a nanoparticulate dry powder Spray drying of the product la) afforded a nanoparticulate dry powder. The active ingredient content in the powder was determined by chromatography to be 9.95 by weight. The dry powder dissolves in drinking water to form a cloudy white dispersion (hydrosol).
Production Example 2 Production of a cyclosporine dry powder with an active ingredient content in the region of 15~ by weight a) Production of the micronisate 3 g of cyclosporine A were stirred into a solution of 0.6 g of ascorbyl palmitate in 18 g of isopropanol and 18 g of deionized water at 25°C. Dissolving was completed by heating w D~r~~~ ,r~a~3$ CA 02388614 2002-04-23 l in a heat exchanger. The cyclosporine solution remained in the heat exchanger for 90 sec, the temperature not exceeding 135°C.
To precipitate the cyclosporine A in colloidal form, this solution was fed at 135°C into a mixing chamber. It was there mixed with 393.9 g of an aqueous solution of 9.2 g gelatin A
100 Bloom and 6.1 g of lactose in deionized water which has been adjusted to pH 9.2 with 1 N NaOH. In order to prevent evaporation of the water, the pressure throughout the process was limited to 30 bar. After mixing, a colloidal dispersion of cyclosporine A was obtained with a cloudy white appearance.
The average particle size was determined by quasielastic light scattering to be 285 nm with a variance of 48~.
Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) = 0.62 ~,m with a fine content of the distribution of 99.8$ <1.22 ~,m.
b) Drying of dispersion 2a) to give a dry powder Spray drying of the dispersion resulted in a nanoparticulate dry powder. The active ingredient content in the dry powder was determined by chromatography to be 15.9$ by weight. The dry powder dissolves in drinking water to form a cloudy white dispersion.
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 376 nm with a variance of 38~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.77 N.m with a fine content of the distribution of 84.7 <1.22 ~,m.
Freeze drying the product resulted in a nanoparticulate dry powder. The active ingredient content in the powder was determined by chromatography to be 16.1$ by weight cyclosporine. The dry powder dissolved in drinking water to give a cloudy white hydrosol.
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 388 nm with a variance of 32$. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) a - 0.79 ~m with a fine content of the distribution of 82.4 < 1. 2 2 dun .
Production Example 3 A colloidal dispersion of cyclosporine A was produced from 4.5 g of cyclosporine A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin A 100 Bloom and 7.2 g of lactose in analogy to Example 2a).
10 The average particle size was determined by quasielastic light scattering to be 280 nm with a variance of 21~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) = 0.62 N.m with a fine content of the distribution of 99.2% <1.22 Vim.
b) Drying of dispersion 3a) to give a nanoparticulate dry powder Spray drying resulted in a nanoparticulate dry powder with a cyclosporine A content (determined by chromatography) of 19.9$ by weight. The dry powder dissolved in drinking water to form a cloudy white dispersion (hydrosol).
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 377 nm with a variance of 45~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.62 ~,m with a fine content of the distribution of 83.3$
<1.22 ~.ttt.
Production Example 4 A preparation was produced employing fish gelatin with molecular weight contents of from 103 to 10~ D as coating matrix material in analogy to Production Example 3.
Production Example 5 Production of a solid solution of cyclosporine by melt extrusion Production took place in a Werner & Pfleiderer ZKS30 twin screw extruder with an output of 2 kg/hour. The still plastic extrudate was shaped by calendering as described in EP-A 240 906. A mixture of 65~ by weight of a polyvinylpyrrolidone with K value 12, 15$
by weight of poloxamer 407 and 20$ by weight of cyclosporine was processed.
005~~50838 CA 02388614 2002-04-23 a Temperature of the sections: 50, 88, 128, 131, 127, 126~C;
Die: 120~C.
The calendered forms were ground using an air jet mill so that 95~ of the particles had a diameter <10 Eun.
Production Example 6 A mixture of 80~ by weight of a copolymer of 60$ by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, and 20~ by weight of cyclosporine was processed in analogy.to Example 5.
Temperature of the sections: 55, 110, 140, 137, 136, 141~C;
Die: 140~C.
Pharmacokinetic properties of the formulations Blood level kinetics in dogs: General method Cyclosporine was administered in the appropriate preparation, either orally as solid form or by gavage in the case of liquid forms, to beagle dogs with a weight in the range from 8 to 12 kg.
Liquid forms were given 50 ml of water, washing down with a further 50 ml of water. Solid forms were administered without water. Feed was withdrawn from the animals 16 h before administration of the substance, and feeding was renewed 4 h after administration of the substance. Blood was taken in heparinized vessels from the jugular vein or the Vena cephalica antebrachii of the dogs before administration of the substance and at intervals up to 32 h. The blood was deep-frozen and stored at -20~C until the analytical workup. The blood levels were determined by a validated, internally standardized GC-MS method.
Form 1 (for comparison):
Sandimmun Optoral, capsule, 100 mg of active ingredient Form 2:
Dry powder from Production Example 2, active ingredient dose 100 mg; administration as hydrosol Form 3:
Extrudate from Production Example 5, active ingredient dose 100 mg; administration as tablet 005/50838 ~ CA 02388614 2002-04-23 Form 4:
Combination of dry powder from Example 2 and extrudate from Example 5, active ingredient dose in the dry powder 50 mg and in the extrudate 50 mg Areas under the curves of the blood levels and relative bioavailability Table Form 1 (Sandimmun Optoral) Para- Dog Dog Dog Dog Dog Dog Mean Median meter 1 2 3 4 5 6 15tmax 2.0 2.0 2.0 1.0 2.0 2.0 2.0 Cmax 1030.0 1062.0 865.0 387.0 1799.0 869.0 1002.0 949.5 AUC 5781.8 6487.8 6497.0 2403.67892.2 7047.8 6018.4 6492.4 AUC/ 734.7 855.9 759.9 288.5 947.4 846.1 738.8 803.0 dose BA $ 99 116 103 39 128 114 100 I00 AUC: Area under the curve BA: Bioavailability tmax: (h]
Cmax: [ng/ml]
Form 2 Para- Dog Dog Dog Dog Dog Dog Mean Median meter ~1 tmax 2.0 1.0 2.0 1.0 2.0 2.0 1.7 2.0 Cmax 488.0 821.0 783.0 985.0 737.0 1088.0 817.0 802.0 AUC 2441.5 3519.8 3712.8 4094.83117.0 4964.5 3641.7 3616.3 AUC/
290.5 423.9 427.0 458.6 349.1 585.8 424.0 429.9 dose %
Form 3 para- Dog Dog Dog Dog Dog Dog Mean Median meter tmax 3.0 2.0 1.0 1.0 2.0 2.0 2.0 1.9 Cmax 692.0 738.0 772.0 1065.0525.0 481.0 715.0 712.6 AUC 2870.5 2830.3 2758.0 3597.31899.0 2003.0 2794.1 2678.9 AUC/ 413.4 441.5 402.7 478.4 341.8 310.5 408.0 399.5 dose $
Form 4 Para- Dog Dog Dog Dog Dog Dog Mean Median meter 1 2 3 4 5 6 tmax 2.0 2.0 0.5 1.0 1.0 1.0 1.0 Cmax 1132.01314.0 6024.0 1013.0 894.0 1579.0 1992.7 1223.0 AUC 4292.05214.3 11519.53931.3 3271.05189.3 5569.5 4740.6 AUC/ 510.7 641.4 1324.7 440.3 366.4 612.3 649.3 561.5 dose BA $ 86 108 222 74 61 103 109 94
The starting materials are accordingly processed together to give a melt which is processed to a homogeneous composition by input of mechanical energy, in particular in the form of shear forces.
The homogeneous melt is then extruded through a die or a breaker plate and shaped. This can take place by cutting off the extrudate by conventional techniques, for example with the aid of rotating knives or by compressed air cutting off, resulting in pellets or granules. It is further possible for the shaping to take place as described in EP-A 240 906, by the extrudate being passed between two counter-rotating calender rolls and being directly shaped to tablets. The melt can likewise be discharged through the open head and, after solidification, where appropriate also ground or further processed by suitable granulating equipment such as rolls or compacting units.
Examples of suitable matrix formers which the second formulations can contain are melt-processable water-soluble or water-swellable polymers. Water-soluble means that at least 1 g of the polymer dissolves in 10 ml of water at 25~C. Water-swellable means that the water uptake at 25~C and 75$ relative humidity is more than 1~
by weight, without the polymer dissolving.
Examples of suitable polymers are homo- and copolymers of N-vinylpyrrolidone with Fikentscher K values of from 19 to 100. A
suitable comonomer is, in particular, vinyl acetate, as is vinyl propionate, vinylcaprolactam or vinylimidazole.
Likewise suitable are cellulose derivatives, for example hydroxyalkylcelluloses such as hydroxypropylcellulose, alkylcelluloses or alkylhydroxyalkylcelluloses such as hydroxypropylmethylcelluloses.
Additionally suitable are polyethylene glycols with molecular weights of from 1500 to 10 million D or polyoxyethylene/polyoxypropylene block copolymers.
It is, of course, also possible to employ mixtures of said polymers.
Also suitable as matrix formers are sugar alcohols such as erythritol, isomalt, mannitol, sorbitol, xylitol or mixtures of such sugar alcohols.
The matrix may also contain pharmaceutically acceptable excipients such as bulking agents, lubricants, mold release agents, flow regulators, plasticizers, dyes, flavorings and/or stabilizers in the amounts customary for this purpose.
In a further embodiment of the invention, the active ingredient dosage forms may comprise a third formulation (component 3). The active ingredient is present in this formulation in the form of particles, the active ingredient in the particles having a crystallinity of at least 20$. The crystallinity refers to the proportion of active substance which is not in amorphous form.
The active ingredient can also be present in component 3 in different crystal modifications.
The active ingredient is present in this formulation in particular as pure crystalline substance without further excipients. The particles have average diameters in the range from 0.05 to 200 dun, preferably 0.1 to 50 Eun. The crystalline particles can be obtained from crude crystalline product by grinding processes known per se. Examples of suitable grinding processes are dry or wet grinding. Examples of suitable apparatus are ball mills, pinned disk mills or air jet mills.
The dosage forms according to the invention are obtained by physically mixing components 1, 2 and 3. The total amount of active ingredient in component 1 is preferably in the range from 10 to 70~ by weight, particularly preferably from 20 to 60$ by weight, in component 2 is preferably in the range from 10 to 70$
by weight, particularly preferably from 20 to 60~ by weight, and in component 3 is preferably in the range from 0 to 30~ by weight. The physical properties of the individual components are unchanged after the mixing.
The physical mixtures according to the invention of two or three preparations of the active ingredient in each of which the active ingredient is present in a different physical form can be employed in all oral drug forms suitable for this purpose. Thus, for example, they can be packed into hard or soft gelatin capsules or be compressed to tablets under conditions known per se.
Surprisingly, the dosage forms according to the invention have bioavailabilities which are higher than those of the individual components. Such a synergistic effect was unexpected for the skilled worker.
w The results of a study on dogs prove the good bioavailability of the dosage form by comparison with a product on the market.
Production Example 1 Production of an active ingredient dry powder with an active ingredient content in the region of 10~ by weight a) Production of the micronisate 3 g of cyclosporine A were stirred into a solution of 0.6 g of ascorbyl palmitate in 36 g of isopropanol at 25°C, resulting in a clear solution.
To precipitate the cyclosporine A in colloidal form, this solution was fed at 25°C into a mixing chamber. It was there mixed with 537 g of an aqueous solution of 14.4 g gelatin B
100 Hloom and 12.6 g of lactose in deionized water which has been adjusted to pH 9.2 with 1 N NaOH. The pressure throughout the process was limited to 30 bar. After mixing, a colloidal dispersion of cyclosporine A was obtained with a cloudy white appearance.
The average particle size was determined by quasielastic light scattering to be 256 nm with a variance of 31~.
Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.62 N,m with a fine content of the distribution of 99.2$ <1.22 ~.m.
b) Drying of dispersion a) to give a nanoparticulate dry powder Spray drying of the product la) afforded a nanoparticulate dry powder. The active ingredient content in the powder was determined by chromatography to be 9.95 by weight. The dry powder dissolves in drinking water to form a cloudy white dispersion (hydrosol).
Production Example 2 Production of a cyclosporine dry powder with an active ingredient content in the region of 15~ by weight a) Production of the micronisate 3 g of cyclosporine A were stirred into a solution of 0.6 g of ascorbyl palmitate in 18 g of isopropanol and 18 g of deionized water at 25°C. Dissolving was completed by heating w D~r~~~ ,r~a~3$ CA 02388614 2002-04-23 l in a heat exchanger. The cyclosporine solution remained in the heat exchanger for 90 sec, the temperature not exceeding 135°C.
To precipitate the cyclosporine A in colloidal form, this solution was fed at 135°C into a mixing chamber. It was there mixed with 393.9 g of an aqueous solution of 9.2 g gelatin A
100 Bloom and 6.1 g of lactose in deionized water which has been adjusted to pH 9.2 with 1 N NaOH. In order to prevent evaporation of the water, the pressure throughout the process was limited to 30 bar. After mixing, a colloidal dispersion of cyclosporine A was obtained with a cloudy white appearance.
The average particle size was determined by quasielastic light scattering to be 285 nm with a variance of 48~.
Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) = 0.62 ~,m with a fine content of the distribution of 99.8$ <1.22 ~,m.
b) Drying of dispersion 2a) to give a dry powder Spray drying of the dispersion resulted in a nanoparticulate dry powder. The active ingredient content in the dry powder was determined by chromatography to be 15.9$ by weight. The dry powder dissolves in drinking water to form a cloudy white dispersion.
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 376 nm with a variance of 38~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.77 N.m with a fine content of the distribution of 84.7 <1.22 ~,m.
Freeze drying the product resulted in a nanoparticulate dry powder. The active ingredient content in the powder was determined by chromatography to be 16.1$ by weight cyclosporine. The dry powder dissolved in drinking water to give a cloudy white hydrosol.
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 388 nm with a variance of 32$. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) a - 0.79 ~m with a fine content of the distribution of 82.4 < 1. 2 2 dun .
Production Example 3 A colloidal dispersion of cyclosporine A was produced from 4.5 g of cyclosporine A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin A 100 Bloom and 7.2 g of lactose in analogy to Example 2a).
10 The average particle size was determined by quasielastic light scattering to be 280 nm with a variance of 21~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) = 0.62 N.m with a fine content of the distribution of 99.2% <1.22 Vim.
b) Drying of dispersion 3a) to give a nanoparticulate dry powder Spray drying resulted in a nanoparticulate dry powder with a cyclosporine A content (determined by chromatography) of 19.9$ by weight. The dry powder dissolved in drinking water to form a cloudy white dispersion (hydrosol).
The average particle size immediately after redispersion was determined by quasielastic light scattering to be 377 nm with a variance of 45~. Fraunhofer diffraction was used to determine the average of the volume distribution to be D(4,3) - 0.62 ~,m with a fine content of the distribution of 83.3$
<1.22 ~.ttt.
Production Example 4 A preparation was produced employing fish gelatin with molecular weight contents of from 103 to 10~ D as coating matrix material in analogy to Production Example 3.
Production Example 5 Production of a solid solution of cyclosporine by melt extrusion Production took place in a Werner & Pfleiderer ZKS30 twin screw extruder with an output of 2 kg/hour. The still plastic extrudate was shaped by calendering as described in EP-A 240 906. A mixture of 65~ by weight of a polyvinylpyrrolidone with K value 12, 15$
by weight of poloxamer 407 and 20$ by weight of cyclosporine was processed.
005~~50838 CA 02388614 2002-04-23 a Temperature of the sections: 50, 88, 128, 131, 127, 126~C;
Die: 120~C.
The calendered forms were ground using an air jet mill so that 95~ of the particles had a diameter <10 Eun.
Production Example 6 A mixture of 80~ by weight of a copolymer of 60$ by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, and 20~ by weight of cyclosporine was processed in analogy.to Example 5.
Temperature of the sections: 55, 110, 140, 137, 136, 141~C;
Die: 140~C.
Pharmacokinetic properties of the formulations Blood level kinetics in dogs: General method Cyclosporine was administered in the appropriate preparation, either orally as solid form or by gavage in the case of liquid forms, to beagle dogs with a weight in the range from 8 to 12 kg.
Liquid forms were given 50 ml of water, washing down with a further 50 ml of water. Solid forms were administered without water. Feed was withdrawn from the animals 16 h before administration of the substance, and feeding was renewed 4 h after administration of the substance. Blood was taken in heparinized vessels from the jugular vein or the Vena cephalica antebrachii of the dogs before administration of the substance and at intervals up to 32 h. The blood was deep-frozen and stored at -20~C until the analytical workup. The blood levels were determined by a validated, internally standardized GC-MS method.
Form 1 (for comparison):
Sandimmun Optoral, capsule, 100 mg of active ingredient Form 2:
Dry powder from Production Example 2, active ingredient dose 100 mg; administration as hydrosol Form 3:
Extrudate from Production Example 5, active ingredient dose 100 mg; administration as tablet 005/50838 ~ CA 02388614 2002-04-23 Form 4:
Combination of dry powder from Example 2 and extrudate from Example 5, active ingredient dose in the dry powder 50 mg and in the extrudate 50 mg Areas under the curves of the blood levels and relative bioavailability Table Form 1 (Sandimmun Optoral) Para- Dog Dog Dog Dog Dog Dog Mean Median meter 1 2 3 4 5 6 15tmax 2.0 2.0 2.0 1.0 2.0 2.0 2.0 Cmax 1030.0 1062.0 865.0 387.0 1799.0 869.0 1002.0 949.5 AUC 5781.8 6487.8 6497.0 2403.67892.2 7047.8 6018.4 6492.4 AUC/ 734.7 855.9 759.9 288.5 947.4 846.1 738.8 803.0 dose BA $ 99 116 103 39 128 114 100 I00 AUC: Area under the curve BA: Bioavailability tmax: (h]
Cmax: [ng/ml]
Form 2 Para- Dog Dog Dog Dog Dog Dog Mean Median meter ~1 tmax 2.0 1.0 2.0 1.0 2.0 2.0 1.7 2.0 Cmax 488.0 821.0 783.0 985.0 737.0 1088.0 817.0 802.0 AUC 2441.5 3519.8 3712.8 4094.83117.0 4964.5 3641.7 3616.3 AUC/
290.5 423.9 427.0 458.6 349.1 585.8 424.0 429.9 dose %
Form 3 para- Dog Dog Dog Dog Dog Dog Mean Median meter tmax 3.0 2.0 1.0 1.0 2.0 2.0 2.0 1.9 Cmax 692.0 738.0 772.0 1065.0525.0 481.0 715.0 712.6 AUC 2870.5 2830.3 2758.0 3597.31899.0 2003.0 2794.1 2678.9 AUC/ 413.4 441.5 402.7 478.4 341.8 310.5 408.0 399.5 dose $
Form 4 Para- Dog Dog Dog Dog Dog Dog Mean Median meter 1 2 3 4 5 6 tmax 2.0 2.0 0.5 1.0 1.0 1.0 1.0 Cmax 1132.01314.0 6024.0 1013.0 894.0 1579.0 1992.7 1223.0 AUC 4292.05214.3 11519.53931.3 3271.05189.3 5569.5 4740.6 AUC/ 510.7 641.4 1324.7 440.3 366.4 612.3 649.3 561.5 dose BA $ 86 108 222 74 61 103 109 94
Claims (11)
1. A solid pharmaceutical dosage form comprising an active ingredient in the form of a physical mixture of at least two preparations which differ in relation to the physical state of the active ingredient.
2. A solid dosage form as claimed in claim 1, comprising a first preparation (component 1) in which the active ingredient is colloidally embedded in the form of solid X-ray amorphous particles in a coating matrix, and a second preparation (component 2) in which the active ingredient is in the form of a molecular dispersion in an excipient matrix.
3. A solid dosage form as claimed in claim 1 or 2, comprising a third preparation (component 3) differing in relation to the physical state of the active ingredient.
4. A solid dosage form as claimed in any of claims 1 to 3, comprising as component 3 active ingredient particles in which the active ingredient has a degree of crystallinity of at least 20%.
5. A solid dosage form as claimed in any of claims 1 to 3, in which the active ingredient particles of component 1 have an average particle diameter of 0.02 to 1 µm.
6. A solid dosage form as claimed in any of claims 1 to 4, in which the coating matrix of component 1 consists of one or more polymeric protective colloids.
7. A solid dosage form as claimed in any of claims 1 to 5, in which the excipient matrix of component 2 comprises one or more than one water-soluble polymer.
8. A solid dosage form as claimed in any of claims 1 to 7, comprising from 10 to 90% by weight of active ingredient in component 1 and from 10 to 90% by weight of active ingredient in component 2.
9. A solid dosage form as claimed in any of claims 1 to 4, where component 3 is present in different crystal modifications.
10. A solid dosage form as claimed in any of claims 1 to 8, comprising from 20 to 60% by weight of active ingredient in component 1, from 20 to 60% by weight of active ingredient in component 2 and from 0 to 30% by weight of active ingredient in component 3.
11. A solid dosage form as claimed in any of claims 1 to 9, comprising cyclosporine as active ingredient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19951617.0 | 1999-10-26 | ||
| DE19951617A DE19951617A1 (en) | 1999-10-26 | 1999-10-26 | Preparations of active pharmaceutical ingredients |
| PCT/EP2000/010205 WO2001030372A2 (en) | 1999-10-26 | 2000-10-17 | Pharmaceutical agent preparations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2388614A1 true CA2388614A1 (en) | 2001-05-03 |
Family
ID=7926968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002388614A Abandoned CA2388614A1 (en) | 1999-10-26 | 2000-10-17 | Pharmaceutical agent preparations |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1223960A2 (en) |
| JP (1) | JP2004500343A (en) |
| CN (1) | CN1384753A (en) |
| CA (1) | CA2388614A1 (en) |
| DE (1) | DE19951617A1 (en) |
| PL (1) | PL354991A1 (en) |
| WO (1) | WO2001030372A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6465016B2 (en) * | 1996-08-22 | 2002-10-15 | Research Triangle Pharmaceuticals | Cyclosporiine particles |
| AR033711A1 (en) * | 2001-05-09 | 2004-01-07 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS |
| DE102005026755A1 (en) * | 2005-06-09 | 2006-12-14 | Basf Ag | Production of solid solutions of sparingly soluble active ingredients by short-term overheating and rapid drying |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0816053B2 (en) * | 1986-12-04 | 1996-02-21 | 大正製薬株式会社 | Method of manufacturing patch |
| JPH0436237A (en) * | 1990-06-01 | 1992-02-06 | Taiho Yakuhin Kogyo Kk | Composite antitumor preparation |
| DE59205625D1 (en) * | 1991-12-05 | 1996-04-11 | Alfatec Pharma Gmbh | PERORAL APPLICATION FOR PEPTIDE DRUGS, IN PARTICULAR INSULIN |
| GB9325445D0 (en) * | 1993-12-13 | 1994-02-16 | Cortecs Ltd | Pharmaceutical formulations |
| JP4189044B2 (en) * | 1997-07-01 | 2008-12-03 | 大正製薬株式会社 | Multiple unit type sustained release tablets |
-
1999
- 1999-10-26 DE DE19951617A patent/DE19951617A1/en not_active Withdrawn
-
2000
- 2000-10-17 CN CN00814940A patent/CN1384753A/en active Pending
- 2000-10-17 JP JP2001532789A patent/JP2004500343A/en not_active Withdrawn
- 2000-10-17 WO PCT/EP2000/010205 patent/WO2001030372A2/en not_active Application Discontinuation
- 2000-10-17 PL PL00354991A patent/PL354991A1/en unknown
- 2000-10-17 CA CA002388614A patent/CA2388614A1/en not_active Abandoned
- 2000-10-17 EP EP00972786A patent/EP1223960A2/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CN1384753A (en) | 2002-12-11 |
| EP1223960A2 (en) | 2002-07-24 |
| WO2001030372A2 (en) | 2001-05-03 |
| JP2004500343A (en) | 2004-01-08 |
| DE19951617A1 (en) | 2001-05-03 |
| PL354991A1 (en) | 2004-03-22 |
| WO2001030372A3 (en) | 2001-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6599528B1 (en) | Mechanically stable pharmaceutical presentations form containing liquid or semisolid surface-active substances | |
| JP6534979B2 (en) | Stable complexes of low solubility compounds | |
| US8349366B2 (en) | Immediate release pharmaceutical granule compositions and a continuous process for making them | |
| US6511681B2 (en) | Aqueous solubility pharmaceutical formulations | |
| JP3722293B2 (en) | Novel pharmaceutical solid dispersion | |
| US7273624B2 (en) | Stable dosage forms containing ubiquinones | |
| KR100694667B1 (en) | Antifungal compositions containing itraconazole with both improved bioavailability and narrow intra- and inter-individual variation of its absorption | |
| WO2017103677A1 (en) | Complexes of celecoxib and its salts and derivatives process for the preparation thereof and pharmaceutical compositions containing them | |
| KR20230107902A (en) | Tablet formulation for cgrp-active compounds | |
| KR100956583B1 (en) | A solid dispersion comprising ubidecarenone, method thereof and pharmaceutical composition comprising the solid dispersion | |
| Aggarwal et al. | Solid dispersion as an eminent strategic approach in solubility enhancement of poorly soluble drugs | |
| JP2013505222A (en) | Fast-dissolving solid pharmaceutical formulations containing amphiphilic copolymers based on polyethers combined with hydrophilic polymers | |
| JP4926319B2 (en) | Solubilizing excipients in powder form for solid pharmaceutical dosage forms | |
| CA2301042A1 (en) | Micro-osmotic controlled drug delivery systems | |
| CA2388614A1 (en) | Pharmaceutical agent preparations | |
| JP2002515415A (en) | Cyclosporine preparation | |
| EP2540281A1 (en) | Solid self-microemulsifying systems | |
| JP2813792B2 (en) | Preparation for oral administration of irsogladine maleate and its production method | |
| KR20210150501A (en) | Solid pharmaceutical composition for treating HCV | |
| MXPA01009542A (en) | Improved aqueous solubility pharmaceutical formulations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |