DE19951617A1 - Preparations of active pharmaceutical ingredients - Google Patents

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

The present invention relates to fixed dosage forms of a active pharmaceutical ingredient in which a physical mixture at least two regarding the physical state of the Active ingredient different preparations of the active ingredient is present. Furthermore, the invention relates to dosage forms, which a third regarding the physical condition of the active ingredient different preparation included.

A whole range of highly effective pharmaceutical ingredients prepares regarding the bioavailability of the dosage forms big problems, especially if in the context of a long-term therapy uniform blood plasma concentrations are desired, but too high blood plasma levels because of the strong side effects must be avoided. For example, this applies to many Immunosuppressants, HIV therapeutics or CNS active substances.

Cyclosporins, a series of non-polar, cyclic oligopeptides, are characterized by their immunosuppressive effect. Under what they gained most from fermentation 11 amino acids, cyclosporin A therapeutic importance won.

Although cyclosporin formulations for both oral and Oral are designed for intravenous use Administration of cyclosporin is preferred because it is better Patient compliance guaranteed.

However, this has a molecular weight of 1202 g / mol quite large cyclosporin A has a high lipophilicity, which expressed at the same time in a very low solubility in water (<0.004% m / V). By a certain solubility in oils like Olive oil as well as in ethanol made it possible to use emulsion concentrates to develop which, when administered orally, to an if also lead to relatively variable, bioavailability of approximately 30% (See R.H. Müller et al. In "Pharmaceutical Technology: Modern Pharmaceutical Forms ", Scientific Publishing Company, Stuttgart, 1997, pp. 118-125).

Peroral forms currently available on the market are demented speaking either emulsion concentrates for administration as Solutions or capsules filled with microemulsions. In both  Cases such as ethanol and / or oil become solu bilization of cyclosporin used.

However, the bioavailability can fluctuate greatly in the range of 10 to 60%. These fluctuations are related to the galenic form and condition the preparation in the gastrointestinal tract. Furthermore, the natural fat digestion has a significant impact on that Absorption of the cyclosporin administered orally.

WO 97/07787 also describes cyclosporin formulations wrote that in addition to the active ingredient, an alkanolic solution agents such as ethanol or propylene glycol and a non-ionic Contain polyoxyalkylene derivative as a surface-active substance.

A disadvantage of such forms is, on the one hand, that they Contain solvents, especially ethanol, on the other hand, that the cyclosporin at low temperatures tends to to recrystallize what in terms of storage stability 1 is problematic. Such precipitates are the widest going to not be absorbed so that a uniform bioavailable may not be guaranteed.

EP-A 425 892 describes a method for improving the Bioavailability of active pharmaceutical ingredients with peptide bindings known, with a solution of the active ingredient in one Water-miscible organic solvent with an aqueous Colloid is quickly mixed so that the active ingredient in colloid disperse form.

In WO 93/10767 there are oral administration forms for peptide Drugs described in which the drug is in the manner is built into a gelatin matrix that the forming colloidal particles are charge neutral. Disadvantageous such forms, however, have a tendency to flocculate.

Furthermore, it is known for example from EP-A 240 904 that Molecularly disperse distributions of an active ingredient in a polymer matrix can be obtained by melt extrusion.

The object of the present invention was for oral administration suitable forms of administration of difficult bioavailable Finding active ingredients such as cyclosporin that are free of solvents and their bioavailability are comparable to the microemulsions.  

The dosage forms defined at the outset were accordingly found in which the active ingredient is in the form of a physical Mix at least two in terms of the physical State of the active ingredient various preparations of the active ingredient substance is present. Pharmaceutical forms were also found in which additionally a third physically different form of action substance is present.

According to the invention, the active ingredient is in a first preparation (Component 1) in the form of solid, X-ray amorphous particles colloi daldispers distributed in a matrix of a polymeric covering material in front. The effect lies in a second preparation (component 2) Molecularly dispersed substance pre-distributed in an auxiliary matrix. In a third physically different form (component 3) the active ingredient is in the form of crystalline particles.

The dosage form according to the invention is suitable in principle for all sparingly water-soluble and hardly bioavailable effects substances, but especially for cyclosporin.

According to the invention, all cyclosporins can be processed before however, cyclosporin A is present. Cyclosporin A has an enamel point from 148 to 151 ° C and becomes a colorless crystalline Substance used.

In component 1, the active ingredient is X-ray amorphous in the form Particles colloidally into one of one or more polymers Stabilizers existing envelope matrix embedded. As a polymer Stabilizers are suitable for swellable protective colloids as with for example beef, pork or fish gelatin, starch, Dextrin, pectin, gum arabic, lignin sulfonates, chitosan, Polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, Carboxymethyl cellulose, hydroxypropyl cellulose, milk powder, Dextran, whole milk or skimmed milk or mixtures of this protection colloid. Homopolymers and copolymers based on are also suitable of the following monomers: ethylene oxide, propylene oxide, acrylic acid, Maleic anhydride, lactic acid, N-vinyl pyrrolidone, vinyl acetate, α- and β-aspartic acid. One of the named is particularly preferred ten types of gelatin used, especially acidic or basic degraded gelatin with bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 as well as low molecular, enzymatically degraded gelatin types the Bloom number 0 and molecular weights from 15000 to 25000 D like for example Collagel A and Gelitasol P (Stoess, Eberbach) and mixtures of these types of gelatin.  

These preparations also contain low molecular weight surface active connections. As such are particularly suitable amphiphilic compounds or mixtures of such compounds. Basically, all surfactants come with an HLB value of 5 to 20 into consideration. As corresponding surface-active substances Examples include: esters of long-chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their Oxyethylation products, esters of monofatty acid glycerides with Acetic acid, citric acid, lactic acid or diacetyltartaric acid, Polyglycerol fatty acid esters such. B. the monostearate of the tri glycerins, sorbitan fatty acid esters, propylene glycol fatty acid esters, 2- (2'-stearoyllactyl) lactic acid salts and lecithin. Prefers Ascorbyl palmitate is used.

The amounts of the various components are according to the invention chosen so that the preparations 0.1 to 70 wt .-%, preferably as 1 to 40 wt .-%, of active ingredient, 1 to 80 wt .-%, preferred 10 to 60 wt .-%, one or more polymeric stabilizers and 0 to 50% by weight, preferably 0.5 to 20% by weight, of one or more contains low molecular weight stabilizers. The weight per percentages refer to a dry powder.

To produce the first form of preparation, a Solution of the active ingredient in a suitable solvent The solution in this context is a real one means molecularly disperse solution or a melt emulsion. Organic water-miscible solvents are suitable as solvents Solvents that are volatile and thermally stable and only Contain carbon, hydrogen, nitrogen and oxygen. 1 Appropriately, they are at least 10% by weight with water miscible and have a boiling point below 200 ° C and / or have less than 10 carbon atoms. Corresponding are preferred suitable alcohols, esters, ketones and acetals. Use in particular one detects ethanol, n-propanol, isopropanol 1,2-butanedio-1-methyl ether, 1,2-propanediol-1-n-propyl ether or acetone.

According to one embodiment of the invention, one becomes molecular disperse solution of the active ingredient in the chosen solvent Temperatures in the range of preferably 20 to 150 ° C, within a period of less than 120 seconds if necessary at an excess pressure of up to 100 bar wise 30 bar, can work.

According to a further preferred embodiment, the action Fabric solution prepared so that the mixture of active ingredient and solvents within a period of less than 10 seconds above the melting point of the active ingredient to 150 to  Heated to 240 ° C, possibly with an overpressure of up to can work at 100 bar, preferably 30 bar.

The concentration of the active ingredient solution thus prepared is generally 10 to 500 g of active ingredient per 1 kg of solvent. In a preferred embodiment of the method is the low molecular stabilizer added directly to the drug solution.

In a subsequent process step, the Active ingredient solution with an aqueous solution of the polymeric shell mixed materials. The concentration of the solution of the polymer Envelope material is 0.1 to 200 g / l, preferably 1 to 100 g / l.

In order to achieve the smallest possible particle sizes during the mixing process, a high mechanical energy input is recommended when ver mix the active ingredient solution with the solution of the shell material. Such energy input can, for example, by strong Stir or shake in a suitable device, or by having the two components with a hard jet injected into a mixing chamber so that it leads to a violent ver mix comes.

The mixing process can be discontinuous or, preferably, continuous done nuously. As a result of the mixing process, there is a Precipitation of the active ingredient in the form of solid, X-ray amorphous Particle. The colloidal suspension thus obtained can then on can be converted into a dry powder in a known manner for example by spray drying, freeze drying or drying in the fluidized bed.

In the preparation of the preparations according to the invention you drive so that the pH of the solution of the shell material, especially of gelatin, and a solution of the active ingredient so sets that none of the active ingredient particles being formed Charge neutrality occurs, i. that is, the pH of the Do not adjust the gelatin solution to such a value that a charge-neutral state is established when the particles are formed. The particles are preferably produced at pH values greater than 7.

The average particle diameter of the solid active ingredient particles in the matrix of the polymeric covering material is 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 Connected to the lack of crystal interference in X-rays powder diagrams (see 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 characterized in that after redispersing a pH value greater than 5 are negatively charged in an aqueous medium.

In the second formulation, the active ingredient is molecular dispersed in an auxiliary matrix. Such molecular disperse distributions of an active ingredient in a matrix also referred to as "fixed solutions" (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300. Such solid solutions can be prepared by the solution process by the active ingredient together with the components forming the auxiliary matrix in be dissolved in a suitable solvent and then the Solvent is removed. Examples of solvents white water, ethanol, isopropanol, acetone, chlorinated coal water substances such as methylene chloride or chloroform, tetrahydrofuran, Toluene or methyl ethyl ketone into consideration. Usually it will Solvent evaporated in vacuo.

Such solid solutions can also be used after melting processes are produced, the active ingredient and the Auxiliary matrix forming ingredients intimately in the melt be mixed. The process is preferred without the addition of Solvents.

The melting process is done in a kneader or a screw extruder carried out. Suitable kneaders are, for example Kneaders from Haake or Farrell.

The melt is preferably produced in one Screw extruder, particularly preferably a twin screw extruders with and without kneading disks or similar mixing elements. Twin screws rotating in the same direction are particularly preferred extruder.

Processing takes place depending on the composition generally at temperatures of 40 to 260 ° C, preferably 50 to 200 ° C.

The feed materials can be used individually or in the extruder or kneader can be supplied as a premix. The addition is preferably carried out in Form of powdered or granulated premixes. So can the liquid or oily surface-active substance beforehand another feed material to form a free-flowing granulate be mixed. An addition of the surfactant in liquid form, for example via liquid pumps, which semi-solid substances are preferably heated, too possible.  

You can also start with the active ingredient in the surfactant Dissolve substance and then mix this mixture with the polymer granu lieren. The active ingredient does not have to melt itself.

It can also be the case with temperature-sensitive active ingredients recommend melting the other feedstocks first and only then add the active ingredient.

The feedstocks accordingly become a melt together processed, which by entering mechanical energy, ins especially in the form of shear forces, to a homogeneous mass is processed.

The homogeneous melt is then passed through a nozzle or a Perforated plate extruded and subjected to shaping. This can by discounting the extrudate emerging in the form of a strand with the usual tee-off techniques take place, for example with the help rotating knife or by hitting compressed air, taking pellets or granules arise. Furthermore, the shape as in described in EP-A 240 906 take place by the strand emerging extrudate between two counter rotating Calender rolls and is formed directly into tablets. The melt can also flow out through the open extruder head will drive and after solidification if necessary still ground be or by suitable pelletizers such as roller mills or compacting units are further processed.

The second preparation forms can be used as suitable matrix formers for example, water-soluble or thermoplastically processable contain water-swellable polymers. Water soluble means that dissolve at least 1 g of the polymer in 10 ml of water at 25 ° C. Water swellable means that the water absorption at 25 ° C and 75% relative humidity is more than 1 wt .-% without the polymer dissolves.

Suitable polymers are, for example, homopolymers and copolymers of N-vinyl pyrrolidones with K values according to Fikentscher from 19 to 100. Particularly suitable comonomers are N-vinyl acetate, also vinyl propionate, vinyl caprolactam or vinyl imidazole.

Cellulose derivatives are also suitable, for example Hydroxyalkyl celluloses such as hydroxypropyl cellulose, alkyl cellulosic or alkyl-hydroxyalkyl celluloses such as hydroxypropyl methyl celluloses.  

Polyethylene glycols with molecular weights are also suitable from 1500 to 10 million D or polyoxyethylene-polyoxypropylene block copolymers.

Of course, mixtures of the poly be used.

Sugar alcohols such as erythritol continue to be used as matrix formers, Isomalt, mannitol, sorbitol, xylitol or mixtures of such sugars alcohols into consideration.

Furthermore, the matrix can still be pharmaceutically acceptable auxiliary substances such as fillers, lubricants, mold release agents, flow regulating agents, plasticizers, colorants, flavorings and / or Stabilizers contained in the usual amounts for this.

According to a further embodiment of the invention, the effects dosage forms a third form of preparation (compo nente 3) included. The effect lies in this preparation substance in the form of particles, the active ingredient in Par particles has a degree of crystallinity of at least 20%. The degree of crystallinity denotes the proportion of the active substance sub punch that is not amorphous. The active ingredient can be in Kompo nente 3 also exist in different crystal modifications.

In particular, the active ingredient is in this formulation as a crystalline pure substance without further auxiliary substances. The particles have average diameters in the range from 0.05 to 200 microns, preferably 0.1 to 50 microns. The crystalline particles can be made from crystalline raw by known grinding processes goods will be received. Suitable grinding processes are, for example Dry or wet grinding. Suitable devices are at for example ball mills, pin mills or air jet mills.

The dosage forms according to the invention are characterized by physi obtain the potassium mixture of components 1, 2 and 3. Prefers the total proportion of active ingredient of component 1 is in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, component 2 in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, and component 3 in the range from 0 to 30% by weight. The physical properties of each Components are unchanged after mixing.

The physical mixtures of two or three preparations of the active substance, in which the active substance each in a different physical form engage in all suitable oral dosage forms. So you can, for example, in hard or soft gelatin  Fill capsules or under known conditions Press tablets.

Surprisingly, the dosage forms according to the invention form bioavailability that is higher than that of the individual components ten lie. Such a synergistic effect was for the specialist not expected.

The results of a dog study prove the good bioavailability Availability of the dosage form compared to a market product.

Production Example 1

Production of an active ingredient dry powder with an active ingredient content in the range of 10% by weight

• a) Production of the micronizate
  3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate in 36 g of isopropanol at 25 ° C., a clear solution being formed.
  To precipitate cyclosporin A in colloidally dispersed form, this molecularly disperse solution was fed to a mixing chamber at 25 ° C. There, the mixture was mixed with 537 g of an aqueous solution of 14.4 g of gelatin B 100 Bloom and 12.6 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The entire process was carried out with a pressure limit of 30 bar. After mixing, a colloidally disperse cyclosporin A dispersion with a white, cloudy shade was obtained.
  The mean particle size was determined to be 256 nm with a variance of 31% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 mm with a fine fraction of the distribution of 99.2 <1.22 mm.
• b) drying the dispersion a) to a nanoparticulate dry powder
  Spray drying of the product 1a) gave a nanoparticulate dry powder. The active substance content in the powder was determined chromatographically at 9.95% by weight. The dry powder dissolves in drinking water to form a white, cloudy dispersion (hydrosol).

Preparation example 2

Production of a cyclosporin dry powder with an active ingredient content in the range of 15% by weight

• a) Production of the micronizate
  3 g of cyclosporin 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. This solution was converted into the molecularly dissolved state by heating in a heat exchanger. The residence time of the cyclosporin solution in the heat exchanger was 90 sec, with a maximum temperature of 135 ° C was not exceeded.
  To precipitate cyclosporin A in colloidally dispersed form, this molecularly disperse solution was fed to a mixing chamber at 135 ° C. There, the mixture was mixed with 393.9 g of an aqueous solution of 9.2 g of gelatin A 100 Bloom and 6.1 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The process was carried out under a pressure limit of 30 bar to prevent the water from evaporating. After mixing, a colloidally disperse cyclosporin A dispersion with a white, cloudy color was obtained.
  The mean particle size was determined to be 285 nm with a variance of 48% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 mm with a fine fraction of the distribution of 99.8% <1.22 mm.
• b) drying the dispersion 2a) to a dry powder
  Spray drying of the dispersion resulted in a nanoparticulate dry powder. The active substance 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 white, cloudy dispersion.
  The mean particle size was determined immediately after redispersion to be 376 nm with a variance of 38% by quasi-elastic light scattering. The mean value of the volume distribution was determined by means of Fraunhofer diffraction to D (4.3) = 0.77 mm with a fine fraction of the distribution of 84.7% <1.22 m.
  Freeze drying of 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 of cyclosporin. The dry powder dissolved in drinking water to form a white, cloudy hydrosol.
  The average particle size was determined by quasi-elastic light scattering immediately after redispersion to be 388 nm with a variance of 32%. The mean value of the volume distribution was determined by means of Fraunhofer diffraction to be D (4.3) = 0.79 mm with a fine fraction of the distribution of 82.4% <1.22 mm.

Preparation example 3

Analogous to example 2a) was a colloidally disperse cyclosporin A dispersion of 4.5 g cyclosporin A, 0.9 g ascorbyl palmitate, 9.6 g of A 100 Bloom gelatin and 7.2 g of lactose were prepared.

The middle particle was created by quasi-elastic light scattering Size determined to 280 nm with a variance of 21%. Means Fraunhofer diffraction became the mean of the volume distribution D (3, 4) = 0.62 mm with a fine fraction of the distribution of 99.2% <1, 2 mm determined.

• a) drying the dispersion 3a) to a nanoparticulate dry powder
  A nanoparticulate dry powder with a cyclosporin A content (determined by chromatography) of 19.9% by weight was obtained by spray drying. The dry powder dissolved in drinking water to form a white cloudy dispersion (hydrosol).
  The mean particle size was determined immediately after redispersion to be 377 nm with a variance of 45% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 mm with a fine fraction of the distribution of 83.3% <1.2 mm.

Preparation example 4

A preparation was produced in the same way as in production example 3, in which fish gelatin with molecular weight fractions of 10 ³ to 10 ⁷ D was used as the coating matrix material.

Preparation example 5

Preparation of a solid solution of cyclosporin by melting extrusion

It was manufactured in a ZKS30 twin-screw extruder from Werner & Pfleiderer with a throughput of 2 kg / hour. The shaping of the still plastic extrudate was carried out as in the EP-A 240 960 described by calendering. Has been processed a mixture of 65 wt .-% of a polyvinylpyrrolidone with the K value 12, 15% by weight of Poloxamer 407 and 20% by weight of cyclosporin. Shot temperature: 50, 88, 128, 131, 127, 126 ° C; Nozzle: 120 ° C.

The calendered molds were made using an air jet mill grind so that 95% of the particles have a diameter <10 microns exhibited.

Preparation example 6

Analogously to Example 5, 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 cyclosporin was processed. Shot temperature: 55, 110, 140, 137, 136, 141 ° C;
Nozzle: 140 ° C.

Pharmacokinetic properties of the preparation forms Blood level kinetics in dogs: general method

Cyclosporin was used in the appropriate preparation beagle dogs weighing in the range of 8 to 12 kg either orally as solid form or by gavage in liquid forms is enough. Liquid forms were placed in 50 ml of water and rinsed with another 50 ml of water. Fixed forms were without Administered water. The animals were given 16 h before the substance was given the feed was withdrawn, feeding was repeated 4 hours later Substance administration. The dogs were given substance before and in the time grid up to 32 h after administration of substance from the jugular vein or the vena Blood drawn from cephalica antebrachii in heparinized vessels. The blood was frozen and pending analytical processing stored at -20 ° C. The blood level was determined by a validated, internally standardized GC-MS method.  

Form 1 (for comparison)

Sandimmun Optoral, capsule, 100 mg active ingredient

Form 2

Dry powder according to preparation example 2, active ingredient dose 100 mg; Administration as a hydrosol

Form 3

Extrudate according to preparation example 5, active ingredient dose 100 mg; Administration as a tablet

Form 4

Combination of dry powder according to Example 2 and extrudate according to Example 5, active ingredient dose in dry powder 50 mg and in the extrudate 50 mg

Areas under the blood level curves and relative bioavailability

table

Form 1 (Sandimmun Optoral)

Form 2

Form 3

Form 4

Claims (11)

1. Solid pharmaceutical dosage form containing one Active ingredient in the form of a physical mixture at least two regarding the physical state of the action of various preparations. 2. Solid dosage form according to claim 1, containing a first Preparation (component 1) in which the active ingredient is in the form solid X-ray amorphous particles in a colloidal dispersion Envelope matrix is embedded, and a second preparation (Component 2) in which the active ingredient is molecularly dispersed in an excipient matrix is present. 3. Solid dosage form according to claim 1 or 2, containing a third regarding the physical state of the action Different preparation (component 3). 4. Solid dosage form according to one of claims 1 to 3, containing as component 3 drug particles in which the Active ingredient has a degree of crystallinity of at least 20% has. 5. Solid dosage form according to one of claims 1 to 3, in of the active ingredient particles of component 1 is a medium one Have particle diameters of 0.02 to 1 µm. 6. Solid dosage form according to one of claims 1 to 4, in which the envelope matrix of component 1 consists of one or more ren polymeric protective colloids. 7. Solid dosage form according to one of claims 1 to 5, in of the excipient matrix of component 2 one or more contains water-soluble polymer. 8. Solid dosage form according to one of claims 1 to 7, containing 10 to 90 wt .-% of the active ingredient in component 1 and 10 to 90% by weight of the active ingredient in component 2.   9. Solid dosage form according to one of claims 1 to 4, component 3 in different crystal modes is present. 10. Solid dosage form according to one of claims 1 to 8, containing 20 to 60% by weight of the active ingredient in component 1, 20 to 60 wt .-% of the active ingredient in component 2 and 0 to 30% by weight of the active ingredient in component 3. 11. Solid dosage form according to one of claims 1 to 9, containing cyclosporin as active ingredient.