DE19848849A1 - Free-flowing, homogeneous spheres of active agent, e.g. drug, in auxiliary matrix, obtained by dropping molten mixture from nozzle into fluid for freezing and solidification - Google Patents

Abstract

In the preparation of solid spheres, comprising active agent(s) (A) homogeneously dispersed in a matrix of at least one auxiliary (B), by mixing (A) with (B) in the melt then extruding and shaping the melt using a nozzle, the melt is dropped from the nozzle by vibrational impulses and the drops are frozen and solidified by contact with a fluid.

Description

The present invention relates to a method for manufacturing of solid, spherical forms that have at least one biological active substance homogeneously dispersed in an excipient matrix included by mixing the biologically active substance with one or more auxiliaries in the melt, and extrusion and shaping the melt by means of a nozzle.

It is common knowledge of preparations of biologically active To produce substances by the melt extrusion process.

The extrusion of active substance-containing melts as an auxiliary substances contain thermoplastically processable polymers for example in EP-A 240 904 or EP-A 240 906 rubbed.

Especially with relatively low-viscosity melts, for example such compositions that have a relatively high proportion of Sugar alcohols or softening agents or gelatin contain, the design causes problems. If you turn convents tional shaping process, the particles tend to ver stick and often have uneven grain sizes. Low viscous preparations show a pronounced flow behave in the melt, so that they do not solidify with the Er rigid comparable to a classic thermoplastic melt is.

EP-B 488 218 discloses particles of special bioabsorbers beer polymer by melting the polymer and connecting the capillary extrusion, the particles in solid can be transferred into a liquid leads, which freezes the particles on contact with it.

From US-A 5 188 838 is known pearl-shaped pharmaceutical Preparations by dropping an active substance-containing melt with the help of a vibrating nozzle and then solidifying the drop in a gas-filled drop tower. A similar The method is described in WO 95/33433.

DE-A 40 07 164 describes a method for freezing flowable matter, especially cell culture suspensions, described in which the culture broth through a nozzle on a cryogenic liquid is sprayed, the nozzle with a Propellant is applied.

The object of the present invention was an improved Ver drive to manufacture solid, spherical shapes containing one or more biological substances in an excipient matrix to provide.

Accordingly, a method for producing solid, spherical forms containing at least one biologically active sub punch homogeneously dispersed in an excipient matrix, by Vermi the biologically active substance with one or more Auxiliary materials in the melt, and extrusion and shaping of the Melt found by means of a nozzle, which is characterized thereby is that the biologically active substance and excipients containing melt dripped by vibration excitation of the nozzle and the drops are frozen by contact with a liquid and be solidified.

According to the invention, solid, spherical shapes stand for pastilles, Pellets or granules, spherical or drop-shaped products.

Mixing the biologically active substance with the auxiliary substances can be done in a manner known per se. The components can be mixed first and then melted and homogenized will. Especially with thermolabile or against shear forces sensitive active ingredients, it is recommended to first Melt auxiliaries and premix and then the effect to mix in fabric.

The melting and mixing takes place in one for this purpose usual device. As mixing and melting devices are common my such devices suitable as they are in the plastic technology can be used. Suitable devices are described for example in "Mixing during manufacture and processing processing of plastics ", H. Pahl, VDI-Verlag, 1986. Especially suitable devices are extruders and dynamic and static cal mixers, as well as stirred tanks, single-shaft agitators with Ab stripping devices, in particular so-called paste mixers, multi-shaft agitators, solid mixers and preferably mixing Kneading reactors, double-bowl kneaders (trough mixers), stamp kneaders (Internal mixer) or rotor / stator systems. Particularly preferred the mixing and melting takes place in one or more screw extruder, in particular a twin screw extruder, kneading chambers can also be connected upstream of this. The Mixing and melting can also take place in such apparatus  take place in which the energy in the form of microwaves or Ultrasound is supplied.

The mixing and melting device can be fed continuously Lich or discontinuously in the usual way. Powder shaped components can in the free inflow, for. B. via a Differential dosing scales are introduced. Plastic masses can NEN fed directly from an extruder or can be fed via a gear pump. Liquid components can be metered in using suitable pump units. Erfin According to the invention, low-viscosity pastes or gels can also be used a high dispersant content are supplied, being as Dispersant is preferably water.

The mixtures are preferably processed into melts at temperatures from 20 to 280 ° C, particularly preferably from 25 to 180 ° C.

For the shaping, the melt is transformed into an even one Vibration offset nozzle guided. There is a division the melt to drop. Such an arrangement is preferred selected, in which several nozzles arranged in a nozzle plate are. The diameter of the nozzles is preferably in the range of 0.1 to 2.2 mm.

The vibration of the nozzle or nozzle plate is carried out with a constant frequency in the range of 50 to 20,000 Hz Vibration excitation can be piezoelectric, magnetic-inductive, mechanically, pneumatically or electro-acoustically. Such Vibration excitation systems are known per se to the person skilled in the art.

The melt should go through the nozzle or nozzle plate have a maximum viscosity of 2000 mPa.s. Are preferred Melt viscosities in the range of 50 to 1000, especially before moves 100 to 600 mPa.s. Due to the surface tension at the demolition At this point, drops are formed, which depend on the nozzle knife a diameter of 0.01 to 30 mm, preferably 0.3 to 3 mm can have. The ratio of nozzle diameter D1 and In the optimal case, drop diameter D2 is D1: D2 = 0.7: 1.

The dropping particles are solidified by having them with a cold liquid medium in which the drops are insoluble are in contact. As a cold liquid medium, ins special liquid gases which are inert towards the shaped bodies, such as liquid nitrogen, liquid air or liquid noble gases are set, with liquid nitrogen being preferred. The Contacting is preferably carried out in such a way that the  Drop diagonally into a storage container with the appropriate cold liquid medium drops by the drops formed by a jet of compressed gas away from the nozzle or nozzle plate be torn. The gas jet is guided accordingly so that he towards the surface of the cryogenic liquid leads. Nitrogen is particularly suitable as a gas, but also air or noble gases such as argon.

After solidification, the spherical moldings produced in this way can who separated from the liquid medium by simple sieving the. Tape devices that are under are also suitable for severing the surface of the cryogenic liquid and the shape body from the cryogenic medium over an endless belt continuously Lich further processing.

The grain sizes of the moldings according to the invention are preferred wise in the range of 0.1 to 5 mm.

The forms obtained by the process according to the invention ent keep the active ingredient as a homogeneous dispersion in an excipient matrix.

The auxiliary matrix comprises at least one thermoplastic ver workable binder, which preferably in physiological Environment is soluble or swellable.

Suitable polymeric matrix components are, for example:
Polyvinyl pyrrolidone (PVP), copolymers of N-vinyl pyrrolidone with vinyl esters, in particular with vinyl acetate, or else with vinyl propionate. The K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58-64 and 71 and 74) are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35. The K are for PVP Values particularly preferably in the range from 17 to 35.

Copolymers of vinyl acetate and crotonic acid, partially saponified Polyvinyl acetate or polyvinyl alcohol.

Cellulose derivatives such as cellulose ethers, in particular Methyl cellulose, ethyl cellulose, hydroxyalkyl celluloses, esp special hydroxypropyl cellulose, hydroxyalkyl alkyl celluloses, especially hydroxypropyl methyl cellulose and hydroxypropyl Ethyl cellulose.  

Cellulose esters such as cellulose phthalates, especially Celluloseace tatphtalat and hydroxypropylmethylcellulose phthalate, further also mannans, especially galactomannans.

Polymers are also suitable as polymeric binders Basis of acrylates or methacrylates, for example those as Eu dragite types known polyarylates and polymethacrylates, copoly merisate of acrylic acid and methyl methacrylate or polyhydroxyal kyl acrylates or methacrylates.

Polycarboxylic acids, polylactides and polyglyko are also suitable lide, polylactide polyglycolide, polydioxane, polyanhydride, poly styrene sulfonates, polyacetates, polycaprolactones, poly (ortho) esters, Polyamines, polyhydroxyalkanoates or alginates.

Suitable matrix components can also be natural or semi-synthetic hetic binders such as starches, degraded starches, for example wise maltodextrin, also gelatin, which depending on the requirements may have basic or acidic character, chitin or be chitosan. Gelatins are preferred.

Low molecular weight binders are also suitable according to the invention as matrix substances, especially sugar alcohols such as, for example Sorbitol, mannitol, xylitol or, particularly preferably, isomalt. Exactly if preferred is also trehalose, which is a cryoprotective we development unfolded.

Fats or waxes can also be used as binders be set. For example, polyethylene glycols are suitable or polypropylene glycols with molecular weights in the range of 300 to 100,000 as binders.

Homo- and copolymers are particularly preferred binders of N-vinyl pyrrolidone, sugar alcohols and gelatin.

Mixtures of the mentioned bandage can of course also be used means are used.

The binder must be in the total mixture of all components in the Soften range from 40 to 180 ° C, preferably 60 to 130 ° C or melt.

A solvent can also be added to the melt, in addition to its solution properties, it is also softening Can have an effect in the melt. Such solvents are above all monohydric or polyhydric alcohols or water or Mixtures of alcohols and water. Preferred softening Water is the solvent. It may be advisable to use the Weichma Adding solvents in amounts of 0.5 to 70 wt .-%. By adding the solvent, the viscosity of the Melt adjusted and thus the tear behavior at the nozzle or nozzle plate can be influenced. When solidifying in the cold liquid medium, which represents freeze drying, the solvent can be removed again. According to the invention melts are processed whose viscosity is lower at 100 ° C than 5000 mPa.s, determined by rotational viscometry.

The inventive method is suitable for processing al biologically active substances that are among the processing do not decompose. Biologically active substances are, for example, active pharmaceutical ingredients, veterinary medicine African active ingredients, dietary supplements or dietary Means, also pesticides or means for the Animal nutrition.

Suitable pharmaceutical active ingredients are, for example
Acebutolol, Acetylcysteine, Acetylsalicylic Acid, Aciclovir, Albra zolam, Albumin, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amiloride, Aminoacetic Acid, Amiodarone, Amitripylline, Amicodolidol, Aicicidolidol, Aicicidolidol, Aicicidolidol, Aoxicidolidol, Aicicidolidol, Aoxicidolidol, Aoxicidol Aid, Aicicidol Aid, Aicicidolidol , Benzalconium Hydroxide, Benzocaine, Benzoic Acid, Betametasone, Bezafibrate, Biotin, Biperiden, Bisoprolol, Brazosin, Bromacepam, Bromhexine, Bromocriptine, Budesonide, Bufexamac, Buflomedil, Buspyrone, Caf fein, Camphor, Cappvproplin, Carbp , Cefatroxil, Cefazolin, Cefixime, Cefota xime, Ceftazidine, Ceftriaxone, Cefuroxime Axetil, Celediline, Chloramphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Choline, Ciclusporin, Cilastatin, Cimetidine, Ciproflatinidhrin, Ciprofloxidin Clonazepam, clonidine, clotrimazole, codeine, colestyr amine, cromoglicic acid, cyanocobalamin, cy proterone, Desoges trel, Dexamethasone, Dexpanthenol, Dexthromethorphan, Dextropro poxiphene, Diazepam, Dichlofenac, Digoxin, Dihydrocodeine, Dihy droergotamine, Dilthiazem, Diphenhydramine, Dipyridamole, Dipy rone, Disopyramapine, Epidrone, Epidrone, Epidrone, Epidrone, Epidrone, Epidrone, Epidrone Erythromycin, Estradiol, Ethinylestradinol, Etoposide, Eucalyptus Globulus, Famotidine, Felodipine, Fenofibrate, Fenoterol, Fentanyl, Flavin Mononucleo tide, Fluconazole, Flunarizine, Fluorouracil, Fluoxetine, Flur biprofen, Glibipincline, Globinocinclinicine, Globinocine, Ginozincline, Globinicine, Globinicine, Globinicine, Globinicine, Globinicine, Globinicine, Ginocinicine, Globinicine, Globinicine, Ginocinicine, Globinicine, Globinicine, Ginocinicine, Glinocinicine, Gibinicine, Ginocinicine, Ginocinicine, Glinocinicine, Ginocinicine, Ginocinicine, Glucinocide , Glycyrrhiza Glabra, Guaife nesin, Haloperidol, Heparin, Hyaluronic Acid, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphone, Ibratropium Hydroxide, Ibuprofen, Imipenem, Indomethacin, lohexol, Iopamidol, Isosorbide Dinitronitrine, Isosetetoleolate, Isosetetol Labatalon, lactulose, leci thin, levocarnitine, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lisinopril, Loperamide, Loraz epam, Lovastatin, Medroxyprogesterone, Menthol, Methotrexate, Methyldopa, Methylprednisolone, Metoglobramide, Metoprolol, Mico nazole, Morycline, Midazoblaminolamine, Midazobolamolamine, Midazolamolamine Minerals, Mystatin, N-Methylephedrine, Naftidro furil, Naproxen, Neomycin, Nicardipine, Nicergoline, Nicotina mide, Nicotine, Nicotinic Acid, Nifedipine, Nimodipine, Nitrendi pine, Nizatidine, Norethisterone, Norfloxacin, Norgestrinline, Norephoxinolone, Nor tripholone, Nor triphole , Pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicil lin V, phenobarbital, phenoxifylline, phenylephrine, phenylpropa nolamin, phenytoim, piroxicam, polymyxin B, povidone iodine, prava statin, prednisineprone, propafenone, propafenone, propafenone Pyridoxine, Quinidine, Ramipril, Ranitidine, Reserpine, Retinol, Riboflavin, Rifampicin, Rutoside, Saccharin, S albutamol, Salcatonin, Salicyl Acid, Simvastatin, Somatropin, Sotalol, Spironolactone, Sucralfate, Sulbactam, Sulfamethoxazole, Sulpiride, Tamoxifen, Tegafur, Teprenone, Terazosin, Terbutaline, Terfenadine, Theophylicol, Triamoline, Thiamine , Triamterene, Trime thoprin, Troxerutin, Uracil, Valproic Acid, Vancomycin, Verapamil, Vitamine E, Volinic Acid, Zidovudine.

Dietary supplements or dietary agents are examples wise vitamins or vitamin / mineral mixtures accordingly the legal provisions applicable to such means. Plant protection products can include herbicides, fungicides or be insecticides.

For example, means for animal nutrition are fish feed formulations such as those used in fish farming in particular will.

The molds produced by the process according to the invention can continue to be customary for the applications mentioned contain substances in the usual quantities for this.

Pharmaceutical excipients are e.g. B. fillers, lubricants, molds release agents, plasticizers, blowing agents, stabilizers, paints substances, extenders, flow agents and their mixtures. Reason In addition, however, these pharmaceutical auxiliaries must not thoughts according to the invention in the digestive juices a gel layer surrounding, gradually dissolving or little restrict the most eroding, disintegrating dosage form.

Examples of fillers are inorganic fillers such as that Oxides of magnesium, aluminum, silicon, titanium etc. in one Concentration from 0.02 to 50, preferably from 0.20 to 20 wt .-% based on the total weight of the dosage form.

Examples of lubricants are stearates of aluminum, calcium and magnesium as well as talc and silicone in one concentration from 0.1 to 5, preferably from 0.1 to 3 wt .-% based on the Total weight of the form.

As a decay accelerator z. B. sodium carboxymethyl starch or crospovidone can be used. Also wetting agents like Sodium lauryl sulfate or sodium docusate can be used.

Examples of plasticizers include low molecular weight Poly (alkylene oxides) such as e.g. B. Poly (ethylene glycols), poly (propylene glycols), poly (ethylene propylene glycols); organic plasticizers with low molecular weight such as glycerin, pentaerythritol, glyce rinmonoacetate, diacetate or triacetate, propylene glycol, sodium diethyl sulfosuccinate etc., added in concentrations of 0.5 to 15, preferably from 0.5 to 5 wt .-% based on the total weight of the dosage form.

Examples of dyes are known azo dyes, organic and inorganic pigments or colorants of natural origin.

Inorganic pigments are preferred in concentrations of 0.001 to 10, preferably from 0.5 to 3 wt .-% based on the total weight of the dosage form.

In addition, other additives can be added which improve the flow properties of the mixture or act as mold release agents, such as. B. animal or vegetable fats, preferably in their hydrogenated form, especially those that are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of C ₁₂ , C ₁₄ , C ₁₆ and C ₁₈ fatty acids are preferred. The same function can also waxes such. B. meet carnauba wax. These additives can be added alone without the addition of fillers or plasticizers. These fats and waxes can advantageously be added alone or together with mono- and / or diglycerides or phosphatides, especially lecithin. The mono- and diglycerides preferably derive from the fat types described above, ie C ₁₂ , C ₁₄ , C ₁₆ and C ₁₈ fatty acids. The total amount of fats, waxes, mono- and diglycerides and / or lecithins is 0.1 to 30, preferably 0.1 to 50% by weight, based on the total weight of the pharmaceutical form.

As flow regulators such. B. Aerosile or Talc Ver find application.

Furthermore, stabilizers can also be added, such as. B. Anti oxidants, light stabilizers, hydroperoxide destroyers, Radical scavengers and stabilizers against microbial attack.

Auxiliaries within the meaning of the invention also include substances to prepare a solid solution with the pharmaceutical Understand active ingredient. These are, for example Pentaerythritol and pentaerythritol tetraacetate, polymers such as. B. Polyethylene or polypropylene oxides and their block copolymers (Poloxamers), phosphatides such as lecithin, homo- and copolymers of Vinyl pyrrolidones, surfactants such as polyoxyethylene 40 stearate as well Citric and succinic acid, bile acids, sterols and others, such as B. at J.L. Ford, Pharm. Acta Helv. 61, 89-88 (1986) give.

Additions of bases are also considered pharmaceutical auxiliaries or acids to control the solubility of an active ingredient (see e.g. B. K. Thoma et al., Pharm. Ind. 51, 98-101 (1989)).

The shape produced using the method according to the invention bodies have uniform grain sizes and are of good homo geneity and good flow behavior. Surprisingly, it happens during freeze-drying of the particles neither to agglomerate the Particles still to a phase separation.

The moldings can be used in a variety of ways. For example, they can be filled into hard gelatin capsules which are used as sachets or drinking granules or as So-called solid drops with the help of suitable dosing devices come into use. Furthermore, the moldings can also be closed Dosage forms such as tablets, suppositories or. . . further to process.

Examples

With the help of the method according to the invention, for example Process the following formulations wisely:  

example 1

Ibuprofen 40% by weight Isomalt F 50% by weight PVP K12 10% by weight

Melt viscosity: 0.2 to 0.75 Pa.s at 145 ° C (n = 4)

Example 2

vitamin C 40% by weight Isomalt F 40% by weight

Melt viscosity: 1 to 3 Pa.s at 140 ° C (n = 4)

Example 3

Ketoprofen 50% by weight water 10% by weight PEG 6000 40% by weight

Melt viscosity: 0.065 to 0.095 Pa.s at 90 ° C (n = 4)

Example 4

Ibuprofen 50% by weight gelatin 35% by weight water 10% by weight Poloxamer 188 5% by weight

Claims (9)

1. A process for the production of solid, spherical forms containing at least one biologically active substance homogeneously dispersed in an excipient matrix, by mixing the biologically active substance with one or more auxiliaries in the melt, extrusion and shaping of the melt by means of a nozzle, thereby characterized in that the melt containing bio logically active substance and auxiliary substances is dripped by vibration of the nozzle and the drops are frozen and solidified by contact with a liquid. 2. The method according to claim 1, characterized in that the Mixing and melting the biologically active substance and with one or more additives in a screw mixer he follows. 3. The method according to claim 1 or 2, characterized in that the liquid is a liquid gas. 4. The method according to one or more of claims 1 to 3, characterized in that the spherical shapes are grain size have in the range of 0.01 to 5 mm. 5. The method according to one or more of claims 1 to 4, characterized in that the auxiliary matrix at least contains a thermoplastic polymer. 6. The method according to claim 5, characterized in that the Polymer is a homo- or copolymer of N-vinyl pyrrolidone. 7. The method according to claim 5, characterized in that the Is polymer gelatin. 8. The method according to any one of claims 1 to 4, characterized records that a sugar as an essential matrix auxiliary alcohol is used. 9. The method according to one or more of claims 1 to 7, characterized in that the excipient matrix trehalose contains.