CA2322629A1 - Method for producing solid, spherical forms containing pharmaceutical active agents in a binder matrix - Google Patents
Method for producing solid, spherical forms containing pharmaceutical active agents in a binder matrix Download PDFInfo
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- CA2322629A1 CA2322629A1 CA002322629A CA2322629A CA2322629A1 CA 2322629 A1 CA2322629 A1 CA 2322629A1 CA 002322629 A CA002322629 A CA 002322629A CA 2322629 A CA2322629 A CA 2322629A CA 2322629 A1 CA2322629 A1 CA 2322629A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- Animal Behavior & Ethology (AREA)
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a method for producing solid, spherical forms containing at least one pharmaceutical active agent homogeneously dispersed in an auxiliary matrix. According to this method, the constituents are mixed to form a melt which is then shaped. The invention is characterised in that at least one pharmaceutical active agent is processed with at least one thermoplastically processable matrix auxiliary to form a homogeneous melt with a viscosity of less than 5000 mPas and in that this melt is shaped into drops using a rotating perforated roll. These drops are then cooled so that they solidify.
Description
METHOD FOR PRODUCING SOLID, SPHERICAL FORMS CONTAINING
PHARMACEUTICAL ACTIVE AGENTS IN A BINDER MATRIX
The present invention relates to a process for producing solid spherical moldings which comprise at least one pharmaceutical active ingredient homogeneously dispersed in a binder matrix by mixing the ingredients to form a melt and subsequently shaping.
EP-A 240 904, EP-A 240 906 and EP-A 358105 disclose that pharmaceutical active ingredients can be processed together with polymeric binders by melt extrusion to give various types of solid drug forms. The shaping takes place in these cases by calendering or hot cut using rotating knives.
However, shaping processes of this type are less suitable for shaping low-viscosity melts as obtained, for example, with formulations comprising sugar alcohols as matrix. In addition, such low-viscosity melts also have a tendency to be tacky, which likewise makes shaping by the above-mentioned processes.
difficult.
EP-A 012 192 discloses an apparatus for extruding free-flowing compositions, and this can preferably be employed for granulation. In this apparatus, the free-flowing composition is converted into drops by means of rotating perforated cylinders.
Corresponding apparatuses are commercially available under the name Rotoformer~ (supplied by Sandvik).
WO 93/25074 describes the formulation of crop protection agents by extrusion and shaping with the aid of such a Rotoformer. The formulations obtainable in this way are cloudy, mostly soft powder granules.
It is an object of the present invention to provide a process for producing solid spherical drug forms which also makes it possible to process low-viscosity melts and results in drug forms with good product properties.
We have found that this object is achieved by a process for producing solid spherical moldings which comprise at least one la pharmaceutical active ingredient homogeneously dispersed in an ancillary substance matrix by mixing the ingredients to form a melt and subsequently shaping, wherein at least one pharmaceutical active ingredient is processed with at least one melt-processable matrix ancillary substance, forming a homogeneous melt with a viscosity of less than 5000 mPas, and °
. 0050/48825 shaping the melt into drops with the aid of a rotating perforated roll which are subsequently solidified by cooling.
The process according to the invention is suitable for all active ingredients which do not decompose under the processing conditions.
The process according to the invention is suitable, for example, for formulating the following substances or their physiologically acceptable salts, it also being possible to generate the salts in situ in the extruder:
- Antiinfectives Aciclovir, aminoglycosides, amphotericin B, azole antimyco-tics, clotrimazole, itraconazole, sepraconazole, clindamycin, cephalosporins, chloramphenicol, erythromycin, 5-fluoroura-cil, etoposide, flucytosine, ganciclovir, griseofulvin, gyra-se inhibitors, isoniazid, lincosamides, mebendazole, meflo-quine, metronidazole, nitroimidazoles, novobiocin, platinum compounds, polymyxin B, praziquantel, pyrimethamine, rifampi-cin, saquinavir, streptomycin, sulfonamides, tetracyclines, trimethoprim, vancomycin, zidovudine;
- Antipyretics, analgesics, antiinflammatory agents, paraceta-mol, ibuprofen, ketoprofen, oxaprozin, acetylsalicyl acid, morphine, propoxyphene, phenylbutazone;
- Antibiotics Rifampicin, griseofulvin, chloramphenicol, cycloserine, eryt hromycin, penicillins such as penicillin G, streptomycin, te tracycline;
- Antiepileptics Hydantoins, carbamazepine;
- Antitussives and antiasthmatics Diphenhydramine;
- Antirheumatics Chloroquine, indomethacin, gold compounds, phenylbutazone, oxyphenbutazone, penicillamine;
- Hypnotics Barbiturates, phenobarbital, zolpidem, dioxopiperidines, ur-Bides;
PHARMACEUTICAL ACTIVE AGENTS IN A BINDER MATRIX
The present invention relates to a process for producing solid spherical moldings which comprise at least one pharmaceutical active ingredient homogeneously dispersed in a binder matrix by mixing the ingredients to form a melt and subsequently shaping.
EP-A 240 904, EP-A 240 906 and EP-A 358105 disclose that pharmaceutical active ingredients can be processed together with polymeric binders by melt extrusion to give various types of solid drug forms. The shaping takes place in these cases by calendering or hot cut using rotating knives.
However, shaping processes of this type are less suitable for shaping low-viscosity melts as obtained, for example, with formulations comprising sugar alcohols as matrix. In addition, such low-viscosity melts also have a tendency to be tacky, which likewise makes shaping by the above-mentioned processes.
difficult.
EP-A 012 192 discloses an apparatus for extruding free-flowing compositions, and this can preferably be employed for granulation. In this apparatus, the free-flowing composition is converted into drops by means of rotating perforated cylinders.
Corresponding apparatuses are commercially available under the name Rotoformer~ (supplied by Sandvik).
WO 93/25074 describes the formulation of crop protection agents by extrusion and shaping with the aid of such a Rotoformer. The formulations obtainable in this way are cloudy, mostly soft powder granules.
It is an object of the present invention to provide a process for producing solid spherical drug forms which also makes it possible to process low-viscosity melts and results in drug forms with good product properties.
We have found that this object is achieved by a process for producing solid spherical moldings which comprise at least one la pharmaceutical active ingredient homogeneously dispersed in an ancillary substance matrix by mixing the ingredients to form a melt and subsequently shaping, wherein at least one pharmaceutical active ingredient is processed with at least one melt-processable matrix ancillary substance, forming a homogeneous melt with a viscosity of less than 5000 mPas, and °
. 0050/48825 shaping the melt into drops with the aid of a rotating perforated roll which are subsequently solidified by cooling.
The process according to the invention is suitable for all active ingredients which do not decompose under the processing conditions.
The process according to the invention is suitable, for example, for formulating the following substances or their physiologically acceptable salts, it also being possible to generate the salts in situ in the extruder:
- Antiinfectives Aciclovir, aminoglycosides, amphotericin B, azole antimyco-tics, clotrimazole, itraconazole, sepraconazole, clindamycin, cephalosporins, chloramphenicol, erythromycin, 5-fluoroura-cil, etoposide, flucytosine, ganciclovir, griseofulvin, gyra-se inhibitors, isoniazid, lincosamides, mebendazole, meflo-quine, metronidazole, nitroimidazoles, novobiocin, platinum compounds, polymyxin B, praziquantel, pyrimethamine, rifampi-cin, saquinavir, streptomycin, sulfonamides, tetracyclines, trimethoprim, vancomycin, zidovudine;
- Antipyretics, analgesics, antiinflammatory agents, paraceta-mol, ibuprofen, ketoprofen, oxaprozin, acetylsalicyl acid, morphine, propoxyphene, phenylbutazone;
- Antibiotics Rifampicin, griseofulvin, chloramphenicol, cycloserine, eryt hromycin, penicillins such as penicillin G, streptomycin, te tracycline;
- Antiepileptics Hydantoins, carbamazepine;
- Antitussives and antiasthmatics Diphenhydramine;
- Antirheumatics Chloroquine, indomethacin, gold compounds, phenylbutazone, oxyphenbutazone, penicillamine;
- Hypnotics Barbiturates, phenobarbital, zolpidem, dioxopiperidines, ur-Bides;
- Psychopharmaceuticals, neuroleptics Perazine, promazine, sulpiride, thioridazine, chlorpromazine, meprobamate, triflupromazine, melperone, clozapine, risperi-done, reserpine;
- Tranquilizers;
- Antidepressants Imipramine, paroxetine, viloxazine, moclobemide;
- Psychostimulants;
- Psychotomimetics;
- Diuretics Potassium canrenoate, loop diuretics, furosemide, hydrochlo-rothiazide, spironolactone, thiazides, triamterene;
- Hormones Androgens, antiandrogens, gestagens, glucocorticoids, estro-gens, cortisol, dexamethasone, prednisolone, testosterone, Adiuretin, oxytocin, somatropin, insulin;
- Immunosuppressants Ciclosporin;
- Bronchodilators;
- Muscle relaxants, tranquilizers Carisoprodol, tetrazepam, diazepam, chlordiazepoxide;
- Enzymes Lipase, phytase;
- Anti-gout agents Allopurinol, colchicine;
- Anticoagulants Coumarins;
- Antiepileptics Phenytoin, phenobarbital, primidone, valproic acid, carbama-zepine;
- Antihistamines Chlorphenoxamine, dimenhydrinate;
' 4 - Antimimetics;
- Antihypertensives, antiarrhythmics Lidocaine, procainamide, quinidine, calcium antagonists, gly-cerol trinitrate, isosorbide dinitrate, isosorbide 5-mononi-trate, pentaerythrityl tetranitrate, nifedipine, diltiazem, felodipine, verapamil, reserpine, minoxidil, captopril, ena-lapril, lisinopril;
- Sympathomimetics Norfenefrine, oxedrine, midodrine, phenylephrine, isoprenali-ne, salbutamol, clenbuterol, ephedrine, tyramine, ~-hlockers such as alprenolol, metoprolol, bisoprolol;
- Antidiabetics Biguanides, sulfonylureas, carbutamide, tolbutamide, glibenc-lamide, metformin, acarbose, troglitazone;
- Iron preparations;
- Vitamins Vitamin C, B, A, D, folic acid;
- ACE inhibitors Captopril, ramipril, enalapril;
- Anabolics;
- Iodine compounds;
- X-ray contrast agents;
- CNS-active compounds;
- Antiparkinson agents Biperiden, benzatropine, amantadine, opioid analgesics, bar-biturates, benzodiazepines, disulfiram, lithium salts, theo-phylline, valproate, neuroleptics;
- Cytostatics;
- Antispasmolytics;
- Vasodilators Naftidrofuryl, pentoxifylline.
It is also possible to obtain preparations of the bioactive substances in the form of solid solutions. The term "solid solutions" is familiar to the skilled worker (see Chiou and Riegelman, J. Pharm. Sci. ~Q, 1281-1302 (1971)). In solid 5 solutions of pharmaceutical active ingredients in polymers or other matrices, the active ingredient is in the form of a molecular dispersion in the matrix.
Preferred active ingredients are non-steroidal antirheumatic agents, opioids and vitamins. Ibuprofen and tramadol hydrochloride are particularly preferred.
The amount of active ingredients in the complete preparation may vary within wide limits depending on the activity, rate of release and solubility. Thus, the active ingredient content may be from 0.1 to 90, preferably 5 to 70, % of the total weight of the preparation. The only condition is that the melts can be processed by the process according to the invention.
The active ingredient is in the form of a homogeneous dispersion, preferably as "solid solution", i.e. molecular dispersion, in an ancillary substance matrix.
Suitable components for the ancillary substance matrix may be polymeric or else low molecular weight binders as long as they are melt-processable without decomposition and do not give together with the active ingredient, and other additives where appropriate, solid forms prone to cold flow.
Examples of suitable polymeric matrix components are:
Homo- or copolymers of N-vinylpyrrolidone such as polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone 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 71-74) are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35. The K values for PVP are particularly preferably in the range from 10 to 40.
Copolymers of vinyl acetate and,crotonic acid, partially hydrolyzed polyvinyl acetate or polyvinyl alcohol.
Cellulose derivatives, such as, for example, cellulose ethers, in particular methylcellulose, ethylcellulose, hydroxyalkylcelluloses, especially hydroxypropylcellulose, . CA 02322629 2000-08-31 hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose and hydroxypropylethylcellulose.
Cellulose esters such as cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, in addition mannans, especially galactomannans.
Also suitable as polymeric binders are polymers based on acrylates or methacrylates, for example the polyacrylates and polymethacrylates, copolymers of acrylic acid and methyl methacrylate or polyhydroxyalkyl acrylates or methacrylates, known as Eudragit types.
Likewise suitable are polylactides, polyglycolides, polylactide/polyglycolides, polydioxanes, polyanhydrides, polystyrenesulfonates, polyacetates, polycaprolactones, poly(ortho)esters, polyamines, polyhydroxyalkanoates or alginates.
Suitable matrix components can also be natural or semi-synthetic binders such as starches, degraded starches, for example maltodextrin, in addition gelatin which may, depending on requirements, have basic or acidic characteristics, chitin or chitosan. Gelatins are preferred.
Low molecular weight binders are also suitable according to the invention as matrix ancillary substances, in particular sugar alcohols such as, for example, sorbitol, mannitol, xylitol or, particularly preferably, isomalt. Trehalose is also preferred, and displays a cryoprotective effect.
It is also possible to employ fats or waxes as binders. Thus, suitable examples of binders are polyethylene glycols or.
polypropylene glycols with molecular weights in the range from 300 to 100,000.
Particularly preferred binders are the homo- and copolymers of N-vinylpyrrolidone, sugar alcohols and gelatin.
It is, of course, also possible to employ mixtures of said binders, in particular also mixtures of melt-processable polymers with sugar alcohols.
The binder must soften or melt in the complete mixture of all the components in the range from 40 to 180°C, preferably 60 to 130°C.
It is also possible for the melt to be mixed with a solvent which may, as well as its dissolving properties, also display a plasticizing effect in the melt. Solvents of this type are, in particular, monohydric or polyhydric alcohols or water or 5 mixtures of alcohols and water. Water is the preferred plasticizing solvent. It may be advisable to add the plasticizing solvent in amounts of from 0.5 to 30% by weight. By adding the solvent it is possible to adjust the melt viscosity specifically and thus influence the detachment behavior on the die or die 10 plate. The solvent can be removed during the solidification in the cold liquid medium, which represents a freeze-drying. The melts processed according to the invention have a viscosity at~
120°C below 5000 mPas, preferably 1000 to 4000 mPas (measured with a rotational viscometer with shear rates in the range 10-100°/s).
The forms produced by the process according to the invention may additionally contain the ancillary substances customary for the stated uses in the amounts customary for this purpose.
Examples of ancillary substances for drugs are bulking agents, lubricants, mold release agents, plasticizers, blowing agents, stabilizers, dies, extenders, flowability agents and mixtures thereof. However, the ancillary substances for drugs must never restrict the idea according to the invention of a drug form which gradually dissolves or at least erodes and disintegrates in the digestive fluids and becomes surrounded with a gel layer.
Examples of bulking agents are inorganic bulking agents such as the oxides of magnesium, aluminum, silicon, titanium etc. in a concentration of from 0.02 to 50, preferably 0.20 to 20, % of the total weight of the drug form.
Examples of lubricants are stearates of aluminum, calcium and magnesium, and talc and silicones in a concentration of from 0.1 to 5, preferably from 0.1 to 3, % of the total weight of the form.
Examples of disintegration promotors which can be employed are sodium carboxymethyl starch or crospovidone. It is also possible to employ wetting agents such as sodium lauryl sulfate or sodium docusate.
Examples of plasticizers comprise low molecular weight poly(alkylene oxides), such as, for example, polyethylene glycols), polypropylene glycols), poly(ethylene/propylene glycols); organic plasticizers with a relatively low molecular weight such as glycerol, pentaerythritol, glycerol monoacetate, diacetate or triacetate, propylene glycol, sodium diethyl sulfosuccinate etc., added in concentrations of from 0.5 to 15, preferably from 0.5 to 5, % of the total weight of the drug form.
Examples of dies are known azo dies, organic and inorganic pigments or coloring matter of natural origin.
Inorganic pigments are preferred in concentrations of from 0.001 to 10, preferably from 0.5 to 3, % of the total weight of the drug form.
It is also possible to add other additives which improve the flow properties of the mixture or act as mold release agents, such as, for example, animal or vegetable fats, preferably in their hydrogenated form, especially those which are solid at room temperature. These fats preferably have a melting point of 50°C or above. Triglycerides of the C12, Ci4. Cis and C18 fatty acids are preferred. The same function can also be carried out by waxes such as, for example, carnauba wax. These additives can be added alone without the addition of bulking agents or plasticizers.
These fats and waxes can advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the fat types described above, i.e. C12, C14, Cis and C18 fatty acids. The total amount of fats, waxes, mono- and diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 50, % of the total weight of the drug form.
Examples of flow regulators which can be used are Aerosils or talc.
It is also possible to add stabilizers such as, for example, antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers and stabilizers against microbial attack.
Ancillary substances also mean for the purpose of the invention substances for producing a solid solution with the pharmaceutical active ingredients. Examples of these ancillary substances are pentaerythritol and pentaerythritol tetraacetate, polymers such as, for example, polyethylene oxides or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, in J.L. Ford, Pharm. Acta iielv. ~1, 69-88 (1986).
Pharmaceutical ancillary substances are also regarded as being additions of bases or acids to control the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind.
98-101 (1989)).
The mixing of the bioactive substance with the ancillary substances can take place in a manner known per se. The components can be mixed first and then melted and homogenized.
However, it may be advisable, especially with active ingredients which are thermally unstable or sensitive to shear forces, first to melt and mix the ancillary substances and then mix in the active ingredient.
The melting and mixing take place in an apparatus customary for this purpose. Generally suitable mixing and melting apparatuses are those employed in plastics technology. Suitable apparatuses are described, for example, in ~~Mischen beim Herstellen and Verarbeiten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
Particularly suitable apparatuses are extruders and dynamic and static mixers, and stirred vessels, single-shaft stirrers with stripper mechanisms, especially paste mixers, multi-shaft stirrers, solids mixers and, preferably, mixer/kneader reactors, trough mixers, internal mixers or rotor/stator systems. The mixing and melting particularly preferably take place in a single-screw or multi-screw extruder, in particular a twin-screw extruder, and this can also be preceded by mixing chambers. The mixing and melting can also take place in apparatuses in which the energy is supplied in the form of microwaves or ultrasound.
The charging of the mixing and melting apparatus can take place continuously or batchwise in a conventional way. Powdered components can be fed in freely, for example through a weigh feeder. Plastic compositions can, for example, be fed in directly from an extruder or be fed in via a gear pump. Liquid components can be metered in through suitable pumping units. It is also possible according to the invention to feed in low-viscosity pastes or gels with a high dispersing medium content, with water preferably being used as dispersing medium.
The mixtures are processed to melts preferably at temperatures from 20 to 280°C, particularly preferably from 25 to 180°C.
For the shaping, the still plastic melt is converted with the aid of rotating perforated rolls into drops which are then solidified by cooling.
According to the invention, the plastic mixture is first extruded using a suitable extruder to give a continuous strand. It is moreover possible for any solvents and residual moisture present to be stripped off by means of a vacuum pump during the 5 extrusion. The shape of the extrusion die depends on the required shape. The melt is preferably extruded through round-section dies, with the plastic mixture being extruded as a strand with circular cross-section and discharged into the Rotoformer~ or into an analogous apparatus suitable for producing pastilles.
The plastic melt is in these cases passed through rotating perforated rolls and converted into drops in this way.
The apparatus suitable for making pastilles consists in particular of a rotating, heatable roll which has orifices and which is surrounded by a perforated casing. The roll and perforated casing preferably move in opposite directions.
The process according to the invention is explained below by means of examples.
General procedure The amounts, stated in each of the examples, of active ingredient and matrix ancillary substances were mixed in a co-rotating, closely intermeshing twin-screw extruder (ZSK 40 from Werner &
Pfleiderer, Stuttgart). The temperature in the extruder zones was (in ~C): Zone 1/80; Zone 2/110; Zone 3/150; Zone 4/150; Zone 6/150; Zone 7/150. The screws rotated at ?0 rpm. The throughput was 20 kg/h with residence times of 1-2 min. The melt emerging through a die on the extruder head was introduced through a gear pump into the roll of the Rotoformer~ (type 50.211, Sandvik Process Systems GmbH, Stuttgart). The rotoformer consists of a rotating, heated roll which has a perforated casing through whose perforation the still plastic extrudate was discharged onto a cooled conveyor belt. The perforated casing had 3720 holes (d = 1 mm), and the capacity of the roll is about 2 kg of melt. The distance between the perforated casing and the cooling belt was 3 mm. The cooling belt had a length of 4 m and a width of 400 mm.
The temperature of the roll was kept at 150 to 170°C, the temperature of the belt was adjusted to 20°C by cooling with water, and the belt moved at 30 m/min.
Example 1 Ibuprofen 50 Gew.-%
PVP K30 50 Gew.-%
Example 2:
Ibuprofen 40 Gew.-%
PVP K30 55 Gew.-%
10Copolyvidones 5 Gew.-%
Example 3 Ibuprofen 26 Gew.-%
15Isomalt 74 Gew.-%
(Palatinit~) Temperature of the extruder zones:
in C 20, 80, 120, 80, 80 (die) 80, Example 4 Tramadol hydrochloride 20 Gew.-%
Isomalt 80 Gew.-%
Example 5 Ibuprofen 20 Gew.-%
Na ibuprofenate 44 Gew.-%
30PVP K30 22 Gew.-%
Hydroxypropylmethylcellulose m.w. with a viscosity of 4000 mPas 14 Gew.-%
(Methocel~ K4M, from Colorcon Dow)
- Tranquilizers;
- Antidepressants Imipramine, paroxetine, viloxazine, moclobemide;
- Psychostimulants;
- Psychotomimetics;
- Diuretics Potassium canrenoate, loop diuretics, furosemide, hydrochlo-rothiazide, spironolactone, thiazides, triamterene;
- Hormones Androgens, antiandrogens, gestagens, glucocorticoids, estro-gens, cortisol, dexamethasone, prednisolone, testosterone, Adiuretin, oxytocin, somatropin, insulin;
- Immunosuppressants Ciclosporin;
- Bronchodilators;
- Muscle relaxants, tranquilizers Carisoprodol, tetrazepam, diazepam, chlordiazepoxide;
- Enzymes Lipase, phytase;
- Anti-gout agents Allopurinol, colchicine;
- Anticoagulants Coumarins;
- Antiepileptics Phenytoin, phenobarbital, primidone, valproic acid, carbama-zepine;
- Antihistamines Chlorphenoxamine, dimenhydrinate;
' 4 - Antimimetics;
- Antihypertensives, antiarrhythmics Lidocaine, procainamide, quinidine, calcium antagonists, gly-cerol trinitrate, isosorbide dinitrate, isosorbide 5-mononi-trate, pentaerythrityl tetranitrate, nifedipine, diltiazem, felodipine, verapamil, reserpine, minoxidil, captopril, ena-lapril, lisinopril;
- Sympathomimetics Norfenefrine, oxedrine, midodrine, phenylephrine, isoprenali-ne, salbutamol, clenbuterol, ephedrine, tyramine, ~-hlockers such as alprenolol, metoprolol, bisoprolol;
- Antidiabetics Biguanides, sulfonylureas, carbutamide, tolbutamide, glibenc-lamide, metformin, acarbose, troglitazone;
- Iron preparations;
- Vitamins Vitamin C, B, A, D, folic acid;
- ACE inhibitors Captopril, ramipril, enalapril;
- Anabolics;
- Iodine compounds;
- X-ray contrast agents;
- CNS-active compounds;
- Antiparkinson agents Biperiden, benzatropine, amantadine, opioid analgesics, bar-biturates, benzodiazepines, disulfiram, lithium salts, theo-phylline, valproate, neuroleptics;
- Cytostatics;
- Antispasmolytics;
- Vasodilators Naftidrofuryl, pentoxifylline.
It is also possible to obtain preparations of the bioactive substances in the form of solid solutions. The term "solid solutions" is familiar to the skilled worker (see Chiou and Riegelman, J. Pharm. Sci. ~Q, 1281-1302 (1971)). In solid 5 solutions of pharmaceutical active ingredients in polymers or other matrices, the active ingredient is in the form of a molecular dispersion in the matrix.
Preferred active ingredients are non-steroidal antirheumatic agents, opioids and vitamins. Ibuprofen and tramadol hydrochloride are particularly preferred.
The amount of active ingredients in the complete preparation may vary within wide limits depending on the activity, rate of release and solubility. Thus, the active ingredient content may be from 0.1 to 90, preferably 5 to 70, % of the total weight of the preparation. The only condition is that the melts can be processed by the process according to the invention.
The active ingredient is in the form of a homogeneous dispersion, preferably as "solid solution", i.e. molecular dispersion, in an ancillary substance matrix.
Suitable components for the ancillary substance matrix may be polymeric or else low molecular weight binders as long as they are melt-processable without decomposition and do not give together with the active ingredient, and other additives where appropriate, solid forms prone to cold flow.
Examples of suitable polymeric matrix components are:
Homo- or copolymers of N-vinylpyrrolidone such as polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone 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 71-74) are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35. The K values for PVP are particularly preferably in the range from 10 to 40.
Copolymers of vinyl acetate and,crotonic acid, partially hydrolyzed polyvinyl acetate or polyvinyl alcohol.
Cellulose derivatives, such as, for example, cellulose ethers, in particular methylcellulose, ethylcellulose, hydroxyalkylcelluloses, especially hydroxypropylcellulose, . CA 02322629 2000-08-31 hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose and hydroxypropylethylcellulose.
Cellulose esters such as cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, in addition mannans, especially galactomannans.
Also suitable as polymeric binders are polymers based on acrylates or methacrylates, for example the polyacrylates and polymethacrylates, copolymers of acrylic acid and methyl methacrylate or polyhydroxyalkyl acrylates or methacrylates, known as Eudragit types.
Likewise suitable are polylactides, polyglycolides, polylactide/polyglycolides, polydioxanes, polyanhydrides, polystyrenesulfonates, polyacetates, polycaprolactones, poly(ortho)esters, polyamines, polyhydroxyalkanoates or alginates.
Suitable matrix components can also be natural or semi-synthetic binders such as starches, degraded starches, for example maltodextrin, in addition gelatin which may, depending on requirements, have basic or acidic characteristics, chitin or chitosan. Gelatins are preferred.
Low molecular weight binders are also suitable according to the invention as matrix ancillary substances, in particular sugar alcohols such as, for example, sorbitol, mannitol, xylitol or, particularly preferably, isomalt. Trehalose is also preferred, and displays a cryoprotective effect.
It is also possible to employ fats or waxes as binders. Thus, suitable examples of binders are polyethylene glycols or.
polypropylene glycols with molecular weights in the range from 300 to 100,000.
Particularly preferred binders are the homo- and copolymers of N-vinylpyrrolidone, sugar alcohols and gelatin.
It is, of course, also possible to employ mixtures of said binders, in particular also mixtures of melt-processable polymers with sugar alcohols.
The binder must soften or melt in the complete mixture of all the components in the range from 40 to 180°C, preferably 60 to 130°C.
It is also possible for the melt to be mixed with a solvent which may, as well as its dissolving properties, also display a plasticizing effect in the melt. Solvents of this type are, in particular, monohydric or polyhydric alcohols or water or 5 mixtures of alcohols and water. Water is the preferred plasticizing solvent. It may be advisable to add the plasticizing solvent in amounts of from 0.5 to 30% by weight. By adding the solvent it is possible to adjust the melt viscosity specifically and thus influence the detachment behavior on the die or die 10 plate. The solvent can be removed during the solidification in the cold liquid medium, which represents a freeze-drying. The melts processed according to the invention have a viscosity at~
120°C below 5000 mPas, preferably 1000 to 4000 mPas (measured with a rotational viscometer with shear rates in the range 10-100°/s).
The forms produced by the process according to the invention may additionally contain the ancillary substances customary for the stated uses in the amounts customary for this purpose.
Examples of ancillary substances for drugs are bulking agents, lubricants, mold release agents, plasticizers, blowing agents, stabilizers, dies, extenders, flowability agents and mixtures thereof. However, the ancillary substances for drugs must never restrict the idea according to the invention of a drug form which gradually dissolves or at least erodes and disintegrates in the digestive fluids and becomes surrounded with a gel layer.
Examples of bulking agents are inorganic bulking agents such as the oxides of magnesium, aluminum, silicon, titanium etc. in a concentration of from 0.02 to 50, preferably 0.20 to 20, % of the total weight of the drug form.
Examples of lubricants are stearates of aluminum, calcium and magnesium, and talc and silicones in a concentration of from 0.1 to 5, preferably from 0.1 to 3, % of the total weight of the form.
Examples of disintegration promotors which can be employed are sodium carboxymethyl starch or crospovidone. It is also possible to employ wetting agents such as sodium lauryl sulfate or sodium docusate.
Examples of plasticizers comprise low molecular weight poly(alkylene oxides), such as, for example, polyethylene glycols), polypropylene glycols), poly(ethylene/propylene glycols); organic plasticizers with a relatively low molecular weight such as glycerol, pentaerythritol, glycerol monoacetate, diacetate or triacetate, propylene glycol, sodium diethyl sulfosuccinate etc., added in concentrations of from 0.5 to 15, preferably from 0.5 to 5, % of the total weight of the drug form.
Examples of dies are known azo dies, organic and inorganic pigments or coloring matter of natural origin.
Inorganic pigments are preferred in concentrations of from 0.001 to 10, preferably from 0.5 to 3, % of the total weight of the drug form.
It is also possible to add other additives which improve the flow properties of the mixture or act as mold release agents, such as, for example, animal or vegetable fats, preferably in their hydrogenated form, especially those which are solid at room temperature. These fats preferably have a melting point of 50°C or above. Triglycerides of the C12, Ci4. Cis and C18 fatty acids are preferred. The same function can also be carried out by waxes such as, for example, carnauba wax. These additives can be added alone without the addition of bulking agents or plasticizers.
These fats and waxes can advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the fat types described above, i.e. C12, C14, Cis and C18 fatty acids. The total amount of fats, waxes, mono- and diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 50, % of the total weight of the drug form.
Examples of flow regulators which can be used are Aerosils or talc.
It is also possible to add stabilizers such as, for example, antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers and stabilizers against microbial attack.
Ancillary substances also mean for the purpose of the invention substances for producing a solid solution with the pharmaceutical active ingredients. Examples of these ancillary substances are pentaerythritol and pentaerythritol tetraacetate, polymers such as, for example, polyethylene oxides or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, in J.L. Ford, Pharm. Acta iielv. ~1, 69-88 (1986).
Pharmaceutical ancillary substances are also regarded as being additions of bases or acids to control the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind.
98-101 (1989)).
The mixing of the bioactive substance with the ancillary substances can take place in a manner known per se. The components can be mixed first and then melted and homogenized.
However, it may be advisable, especially with active ingredients which are thermally unstable or sensitive to shear forces, first to melt and mix the ancillary substances and then mix in the active ingredient.
The melting and mixing take place in an apparatus customary for this purpose. Generally suitable mixing and melting apparatuses are those employed in plastics technology. Suitable apparatuses are described, for example, in ~~Mischen beim Herstellen and Verarbeiten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
Particularly suitable apparatuses are extruders and dynamic and static mixers, and stirred vessels, single-shaft stirrers with stripper mechanisms, especially paste mixers, multi-shaft stirrers, solids mixers and, preferably, mixer/kneader reactors, trough mixers, internal mixers or rotor/stator systems. The mixing and melting particularly preferably take place in a single-screw or multi-screw extruder, in particular a twin-screw extruder, and this can also be preceded by mixing chambers. The mixing and melting can also take place in apparatuses in which the energy is supplied in the form of microwaves or ultrasound.
The charging of the mixing and melting apparatus can take place continuously or batchwise in a conventional way. Powdered components can be fed in freely, for example through a weigh feeder. Plastic compositions can, for example, be fed in directly from an extruder or be fed in via a gear pump. Liquid components can be metered in through suitable pumping units. It is also possible according to the invention to feed in low-viscosity pastes or gels with a high dispersing medium content, with water preferably being used as dispersing medium.
The mixtures are processed to melts preferably at temperatures from 20 to 280°C, particularly preferably from 25 to 180°C.
For the shaping, the still plastic melt is converted with the aid of rotating perforated rolls into drops which are then solidified by cooling.
According to the invention, the plastic mixture is first extruded using a suitable extruder to give a continuous strand. It is moreover possible for any solvents and residual moisture present to be stripped off by means of a vacuum pump during the 5 extrusion. The shape of the extrusion die depends on the required shape. The melt is preferably extruded through round-section dies, with the plastic mixture being extruded as a strand with circular cross-section and discharged into the Rotoformer~ or into an analogous apparatus suitable for producing pastilles.
The plastic melt is in these cases passed through rotating perforated rolls and converted into drops in this way.
The apparatus suitable for making pastilles consists in particular of a rotating, heatable roll which has orifices and which is surrounded by a perforated casing. The roll and perforated casing preferably move in opposite directions.
The process according to the invention is explained below by means of examples.
General procedure The amounts, stated in each of the examples, of active ingredient and matrix ancillary substances were mixed in a co-rotating, closely intermeshing twin-screw extruder (ZSK 40 from Werner &
Pfleiderer, Stuttgart). The temperature in the extruder zones was (in ~C): Zone 1/80; Zone 2/110; Zone 3/150; Zone 4/150; Zone 6/150; Zone 7/150. The screws rotated at ?0 rpm. The throughput was 20 kg/h with residence times of 1-2 min. The melt emerging through a die on the extruder head was introduced through a gear pump into the roll of the Rotoformer~ (type 50.211, Sandvik Process Systems GmbH, Stuttgart). The rotoformer consists of a rotating, heated roll which has a perforated casing through whose perforation the still plastic extrudate was discharged onto a cooled conveyor belt. The perforated casing had 3720 holes (d = 1 mm), and the capacity of the roll is about 2 kg of melt. The distance between the perforated casing and the cooling belt was 3 mm. The cooling belt had a length of 4 m and a width of 400 mm.
The temperature of the roll was kept at 150 to 170°C, the temperature of the belt was adjusted to 20°C by cooling with water, and the belt moved at 30 m/min.
Example 1 Ibuprofen 50 Gew.-%
PVP K30 50 Gew.-%
Example 2:
Ibuprofen 40 Gew.-%
PVP K30 55 Gew.-%
10Copolyvidones 5 Gew.-%
Example 3 Ibuprofen 26 Gew.-%
15Isomalt 74 Gew.-%
(Palatinit~) Temperature of the extruder zones:
in C 20, 80, 120, 80, 80 (die) 80, Example 4 Tramadol hydrochloride 20 Gew.-%
Isomalt 80 Gew.-%
Example 5 Ibuprofen 20 Gew.-%
Na ibuprofenate 44 Gew.-%
30PVP K30 22 Gew.-%
Hydroxypropylmethylcellulose m.w. with a viscosity of 4000 mPas 14 Gew.-%
(Methocel~ K4M, from Colorcon Dow)
Claims (3)
we claim:
1. A process for producing solid spherical moldings which comprise at least one pharmaceutical active ingredient homogeneously dispersed in an ancillary substance matrix by mixing the ingredients to form a melt and subsequently shaping, wherein at least one pharmaceutical active ingredient is processed with at least one melt-processable matrix ancillary substance, forming a homogeneous melt with a viscosity of less than 5000 mPas, and shaping the melt into drops with the aid of a rotating perforated roll which are subsequently solidified by cooling.
2. A process as claimed in claim 1, wherein sugar alcohols are employed as matrix ancillary substances.
3. A process as claimed in claim 1 or 2, wherein isomalt is employed as matrix ancillary substance.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19809242.3 | 1998-03-05 | ||
| DE19809242A DE19809242A1 (en) | 1998-03-05 | 1998-03-05 | Process for the production of solid, spherical shaped articles containing pharmaceutical active substances in a binder matrix |
| PCT/EP1999/001271 WO1999044588A2 (en) | 1998-03-05 | 1999-02-26 | Method for producing solid, spherical forms containing pharmaceutical active agents in a binder matrix |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2322629A1 true CA2322629A1 (en) | 1999-09-10 |
Family
ID=7859688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002322629A Abandoned CA2322629A1 (en) | 1998-03-05 | 1999-02-26 | Method for producing solid, spherical forms containing pharmaceutical active agents in a binder matrix |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1059914A2 (en) |
| CA (1) | CA2322629A1 (en) |
| DE (1) | DE19809242A1 (en) |
| WO (1) | WO1999044588A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631325A (en) * | 2004-08-12 | 2012-08-15 | 利洁时保健（英国）有限公司 | Granules comprising a nsaid and a sugar alcohol made by melt extrusion |
| US8349229B2 (en) | 2007-12-11 | 2013-01-08 | Sandvik Materials Technology Deutschland Gmbh | Method and drop former for producing tablets and method for producing a sulfurous fertilizer |
| US8486447B2 (en) | 2003-02-03 | 2013-07-16 | Novartis Ag | Pharmaceutical formulation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19943501A1 (en) * | 1999-09-10 | 2001-03-15 | Basf Ag | Underwater granulation of melts containing active ingredients |
| US20010036959A1 (en) * | 2000-04-03 | 2001-11-01 | Gabel Rolf Dieter | Carvedilol-hydrophilic solutions |
| GB0113841D0 (en) * | 2001-06-07 | 2001-08-01 | Boots Co Plc | Therapeutic agents |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3139920A1 (en) * | 1981-10-08 | 1983-04-28 | Nittner, Erich, Dr., 8280 Kreuzlingen | Agent in the form of granules based on polysaccharide gums, process for the preparation thereof and use |
| DE3813756C1 (en) * | 1988-04-23 | 1989-03-02 | Santrade Ltd., Luzern, Ch | |
| TW230742B (en) * | 1992-06-16 | 1994-09-21 | Du Pont | |
| DE4225730C2 (en) * | 1992-08-04 | 2003-04-30 | Merz Pharma Gmbh & Co Kgaa | Process for the preparation of solid dosage forms with protracted 2-stage release |
| DE19536394A1 (en) * | 1995-09-29 | 1997-04-03 | Basf Ag | Solid pharmaceutical forms, obtainable by extrusion of a polymer-active substance melt containing isomalt |
| DE19753300A1 (en) * | 1997-12-01 | 1999-06-02 | Basf Ag | Process for the preparation of solid dosage forms |
-
1998
- 1998-03-05 DE DE19809242A patent/DE19809242A1/en not_active Withdrawn
-
1999
- 1999-02-26 EP EP99911718A patent/EP1059914A2/en not_active Withdrawn
- 1999-02-26 WO PCT/EP1999/001271 patent/WO1999044588A2/en not_active Ceased
- 1999-02-26 CA CA002322629A patent/CA2322629A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8486447B2 (en) | 2003-02-03 | 2013-07-16 | Novartis Ag | Pharmaceutical formulation |
| CN102631325A (en) * | 2004-08-12 | 2012-08-15 | 利洁时保健（英国）有限公司 | Granules comprising a nsaid and a sugar alcohol made by melt extrusion |
| CN102784113A (en) * | 2004-08-12 | 2012-11-21 | 利洁时保健（英国）有限公司 | Granules comprising a nsaid and a sugar alcohol made by melt extrusion |
| US8349229B2 (en) | 2007-12-11 | 2013-01-08 | Sandvik Materials Technology Deutschland Gmbh | Method and drop former for producing tablets and method for producing a sulfurous fertilizer |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999044588A3 (en) | 1999-10-28 |
| EP1059914A2 (en) | 2000-12-20 |
| WO1999044588A2 (en) | 1999-09-10 |
| DE19809242A1 (en) | 1999-09-09 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |