AT511581A1 - Oral retardant formulation - Google Patents

Oral retardant formulation Download PDF

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Publication number
AT511581A1
AT511581A1 AT7722011A AT7722011A AT511581A1 AT 511581 A1 AT511581 A1 AT 511581A1 AT 7722011 A AT7722011 A AT 7722011A AT 7722011 A AT7722011 A AT 7722011A AT 511581 A1 AT511581 A1 AT 511581A1
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matrix
characterized
formulation
formulation according
retarding
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AT7722011A
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German (de)
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G L Pharma Gmbh
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Abstract

Disclosed is an oral sustained-release formulation containing at least one retarding matrix with at least one active pharmaceutical agent admixed with this matrix, the retarding matrix being based on a hot-extrudable pharmaceutically acceptable salt of 10-20 C-saturated fatty acid and less than 1.0%. Composition, more preferably less than 0.6% by weight, based on the total weight of the formulation, of residual moisture content of solvents, and a method for producing such a formulation.

Description

• · · ft ···! * · · • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. · · »Ft ft * 1

The present invention relates to an oral retarding formulation containing at least one retarding matrix with at least one active pharmaceutical active compound mixed with this matrix.

The term "retarding formulation" as used hereinafter refers to a dosage form in which the active pharmaceutical agent is released more slowly. Such dosage forms are preferably administered orally. Typical representatives are tablets with a special coating which completely dissolves after ingestion neither in the stomach nor in the intestine and which releases the active ingredient by diffusion over a period of several hours. Typical representatives also include sustained-release capsules which contain small active-ingredient sustained-release beads or pellets which are released after dissolution of the capsule shell. Also possible are pharmaceutical forms in which such pellets or pellets are pressed into tablets, such dosage forms are also referred to as Multiple Unit Pellet System (MUPS). Further dosage forms store the active pharmaceutical active ingredient in matrices that die at different rates.

Such retarding formulations may provide well-defined time lapses of the release of the active pharmaceutical agent or optionally also of several active pharmaceutical agents. Common names of the different types of release are slow release, sustained release or prolonged release, and delayed release, respectively. Optionally, retarding formulations may also be combined with a fast-acting starting dose in the dosage forms.

If an active pharmaceutical active substance is mentioned below, this also means a combination of different active substances, such as may be provided, for example, in the case of synergistic effects or a desired simultaneous administration of the various medicaments.

A preferred field of application of oral retarding formulations is pain therapy. The primary goal of modern pain therapy is the individually appropriate relief of severe pain that should occur as quickly and sustainably as possible. This therapeutic goal is dependent on a number of factors, on the one hand, the correct selection of the analgesic active substance is of crucial importance, on the other hand contribute to the chosen dosage form and of course their correct application also to the therapeutic success.

Recently, the WHO phasing scheme developed in 1986 for the treatment of cancer pain has been the subject of much controversy and, in the light of recent findings on the development of pain, even considered to be too rigid by some pain therapists. The WHO Scheme has three levels:

Stage 1 provides for the use of non-opioid analgesics such as paracetamol, ibuprofen, and diclofenac to relieve mild to moderate pain, possibly with the co-administration of a co-analgesic.

Stage 2 includes low potency opioids such as tramadol, dihydrocodeine and tilidine / naloxone.

For extremely severe pain, highly effective opioids such as morphine, fentanyl, oxycodone, buprenorphine, nicomorphine and hydromorphone are used at level 3, unless pain relief was achieved with the previous treatment. As " co-analgetics " It is also possible to use adjuvants such as, for example, antidepressants, neuroleptics or anticonvulsants.

Sufficient analgesia for the most severe pain was not always possible a few years ago. This was mainly due to the enormously fluctuating plasma concentrations due to the short half-lives of the opioids, which last from about two to five hours and the four to six times daily administration of peroral drug forms such as tablets. Capsules or drops or suppositories necessary. Patient compliance was also reduced.

Only the development of peroral opioid sustained-release formulations, which allow for once or twice daily administration and lead to greatly reduced peak-through fluctuation as extent of fluctuations between the maximum and minimum steady-state plasma concentrations, revolutionized pain therapy. These sustained-release formulations quickly became part of the treatment guidelines and have become indispensable in modern pain therapy. Thus, for the sustained release of morphine not only from hydrophobic (cetylstearyl alcohol) and hydrophilic elements (methylhydroxypropylcellulose) existing matrix formulations, but also capsules with slow release pellets are used, the diffusion coatings are in turn based on ethylcellulose. In addition to these slow-release morphine supplements, which allow a twice-daily dose, there are also drugs on the market that can be stimulated by the additional strengthening of the retarding agent. · »« 4 · «* * * '* * ··· ** · · * * * * * * ** * * * * ♦ ·· *» 3

Effects are suitable for once-daily administration of morphine. For example, capsules with fat matrix-based sustained-release granules are available, as well as capsules with sustained-release pellets, whose retarding effect is achieved with ammonium methacrylate copolymer, thus enabling once-daily administration of morphine.

Another oxycodone-containing preparation uses the galenic AcroContin® system, a combined retarding principle with a matrix technology based on ammonium methacrylate copolymer Eudragit® RS and stearyl alcohol. This technology allows for biphasic absorption, ie rapid onset, then delayed release of oxycodone with absorption half-lives of 37 minutes and 6.3 hours. This preparation also allows only twice daily oxycodone.

Extrusion is a common process for the preparation of pharmaceutical formulations in the form of mostly cylindrical moldings. Classically, the moisture extrusion is used to produce such pellets. In doing so, powdered material or preparation is typically wetted with as much suitable solvent (e.g., water or an alcohol as ethanol or mixtures thereof) until a moisture level of 22.0% -22.5% is achieved. The mass is subsequently extruded. In a further process step, the extrudates can be rounded into pellets and then dried. The disadvantage here is that in the moisture extrusion, a solvent which is at least partially soluble in the solvent used is partially dissolved and then recrystallized again during drying of the pellets. The dissolution of the drug, or generally the contact with e.g. Water, ethanol or an ethanol / water mixture may also be detrimental to the stability of the drug if it is sensitive to this. Partial dissolution and recrystallization in the course of moisture extrusion would also allow solvent molecules to be incorporated into the crystal lattice of the drug and, subsequently, e.g. create a pseudo-polymorph, which could also affect the dissolution behavior of the drug from the pellets.

Melt extrusion is a process in which the raw material used is mixed, melted or softened by thermal loading in a cylindrical container having one or more rotating screws and, under defined conditions, into a product of homogeneous density and shape is transformed. The carrier matrix employed, together with the active ingredient and functional additives (e.g., plasticizers, surfactants, anti-adhesives), is preferably processed above the glass transition temperature and mixed at the molecular level. The used * i I * «» »« * «

4

Material must deform easily during the extrusion process and solidify at the end of the process. In melt extrusion, the number of steps for making a dosage form is minimized compared to other methods. For an efficient melting process, polymers having a low melt viscosity and a high thermal conductivity are commonly used. The process conditions depend on the chemical stability, the physical properties, the molecular weight, the glass transition temperature and the melting point. Preferably used are co-rotating twin-screw extruders which are designed so that the screws mesh with each other and thereby clean each other. Since the design of the screw exerts a major influence on the process, melt extruders are usually modular. The dimensions of a screw are expressed by the L / D ratio (length / diameter), which is usually 20: 1 and 40: 1, respectively.

The screw of an extruder typically consists of three sections, namely i) feeding zone, ii) compression zone and iii) metering zone. The input zone has the task to convey the powder from the hopper into the screw; it is characterized by a high channel depth (distance between the cylinder wall and the screw). In the compression or melting zone, the material is compressed and displaced air displaced. This is achieved by a narrowing channel depth or a narrowing flight depth. Likewise, the mass melts in this zone or at least softens. The melt reaches the ejection zone, which is designed to equalize the pulsating flow of the melt to achieve a continuous flow rate through the mesh plate; the flow rate (continuous flow rate) is determined by the channel depth and the length of the ejection zone. Within a few minutes, the material can be transported through the extruder without decomposing the drug or the respective carrier substances by too long a thermal load. The resulting extrudate is comminuted by the process of Heißabschlages into pellets or cylinders. An example of the structure of the interior of a melt extruder is shown in Fig.1. The oral retarding formulations mentioned at the outset, which are used, for example, in pain therapy, could be prepared by such a melt extrusion process, which does not require the use of solvents.

In the general state of the art with regard to melt extrusion of pharmaceuticals, four documents are of particular interest. The review by Chaudhari at http://www.pharmainfo.net/reviews/melt-granulation-technique-review mentions in this regard with regard to • • • * * * * * * * * 4 * · · ♦ · · · «* ···················································· "5"

Among others, melt extrusion expressly indicates the utility of stearic acid and glycerol monostearate as a hydrophilic meltable binder. Miyagawa Y, Okabe T, Yamaguchi Y. Controlled release of diclofenac sodium from wax matrix granules, J Pharm Sei. 1996; 138: 215-224 and Sato H, Miyagawa Y, Okabe T. Dissolution mechanism of diclofenac sodium from wax matrix granules, J Pharm Sei. 1997; 86: 929-934 report the use of another wax, carnauba wax, to make granules with a wax matrix.

WO 2007/085637 A1 to Euroceltique relates to tamper-resistant dosage forms which can not be easily extracted. In this case, the matrix used comprises hydrophobic material and at least one fatty acid, as an active ingredient, among other opioids also called nicomorphine. Again, the matrix formulations can be prepared, for example, according to page 15, lines 15-20 by melt extrusion.

In general, a variety of documents describe pharmaceutical sustained release dosage forms, which can be prepared for example by melt extrusion. The matrices used are mostly hydrophobic fusible carriers from the group of natural or synthetic waxes, fatty acids, fatty alcohols, polymers and mixtures thereof, e.g. in EP 785 775 A2, EP 1 658 054 A2, EP 1 897 545 A2, EP 1 492 506 A2, EP 1 771 160 A2, EP 2 001 445 A2 or also in WO 2009/092818 A1. Some of the documents mentioned also relate to drugs that are resistant to abuse, ie medicines from which the active pharmaceutical active ingredients contained are difficult or impossible to separate again.

If the terms " formulation " or " matrix " are used, so under " formulation " for the purposes of the present invention, an optionally processed mixture of carrier, active pharmaceutical active ingredient and optionally functional additives, excipients and / or fillers to understand. Accordingly, a formulation in the sense of the present invention may also be a pellet or a cylindrical structure that results from the process of hot or melt extrusion (these terms are used synonymously). A " formulation " can either be provided for direct administration, on the other hand tablets can be pressed from the formulation, or even capsules are filled. Under " Matrix " the entirety is understood to mean carrier substance (matrix former), plasticizer or plasticizer and optionally further constituents, in any case without active pharmaceutical active ingredient (API). The " Matrix " is to be regarded as the skeleton of the formulation in which the active substance or API can be incorporated.

Any reference to any active pharmaceutical agent, e.g. A drug, an opioid agonist, an opioid antagonist or an antidote, unless otherwise specified, is intended to include any pharmaceutically acceptable form of such a pharmaceutical agent, such as e.g. the free form, any pharmaceutically acceptable set thereof, any pharmaceutically acceptable basic form, any pharmaceutically acceptable hydrate, pharmaceutically acceptable solvate, stereoisomer, optical isomer or prodrug of the pharmaceutically active substance and any pharmaceutically acceptable analog of such pharmaceutically active ingredient and mixtures of two or more of the foregoing.

The term "pharmaceutically acceptable salt" as used herein may be a salt formed from an acidic or basic group such as a nitrogen group, an active agent or an antidote. Examples of such salts generally include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate , Pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzylsulfonate, p-toluenesulfonate, glubionate and palmitate (ie, 1,1'-methylene). bis (2-hydroxy-3-naphthoate) salts. The term "pharmaceutically acceptable salt " may alternatively be a salt prepared from an active agent or an antidote having an acidic functional group such as a carboxylic acid group or a sulfonic acid functional group and a pharmaceutically acceptable inorganic or organic base. Examples of such bases generally include, but are not limited to, hydroxides of alkali metals, e.g. Sodium, potassium and lithium; Hydroxides of alkaline earth metals, e.g. Calcium and magnesium; Hydroxides of other metals, e.g. Aluminum and zinc; Ammonia and organic amines such as e.g. unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamines; tributylamine; pyridine; N-methylamine, N-ethylamine; Diethytamin; triethylamine; Mono, bis or tris (2-hydroxy lower alkyl amines), e.g. Mono, bis or tris (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) methylamine, N, N, -di-lower alkyl-N- (hydroxy-lower alkyl) -amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri (2-hydroxyethyl) amine; N-methyl-D-glucamine and amino acids such as e.g. Arginine, lysine and the like.

The term "drug" as used herein refers to a pharmaceutical agent that causes a biological effect when absorbed in sufficient quantity into the bloodstream of a patient.

The term "antidote" as used herein refers to a pharmaceutical agent that partially or completely abrogates or reverses at least one biological effect of the drug present in the dosage form, e.g. the euphoric effect, or one or more unpleasant physiological reactions, e.g. Passing on, nausea, diarrhea, causing bad taste when it is in sufficient amount in the bloodstream of a patient or animal.

The term "opioid agonist" as used herein refers to an agent which optionally stereospecifically binds to one or more subspecies of opioid receptors and produces agonist activity.

The term "opioid antagonist" as used herein refers to an antidote that has at least one biological effect of an opioid agonist, e.g. the euphoric effect, either reduced, delayed or reversed, when absorbed in a sufficient amount in the bloodstream of a patient or animal.

The object of the present invention is therefore, starting from the general state of the art as stated above, to provide an oral retarding formulation which is based on an alternative, easily processable, inexpensive and pharmaceutically acceptable matrix and in which those associated with the production by means of moisture extrusion mentioned disadvantages are avoided.

This object is achieved according to the invention in that the retarding matrix is based on a pharmaceutically acceptable salt of a saturable fatty acid with 10-26, preferably 10-20, C atoms to be hot-extrudable and less than 1.0% by weight, particularly preferably less than 0.6 % By weight, based on the total mass of the formulation, of residual moisture content of solvents. The residual moisture content (where "moisture" residues on water, alcohol such as ethanol or mixtures thereof) is understood, for example, by means of a thermobalance after 2 weeks of drying the formulation in the desiccator or after drying the formulation in the fluidized bed at 40 ° C for 30 minutes. By the thermobalance the total moisture content is determined, in which also a possible content of water / (solvent) in the active substance (eg water of hydration) or in used auxiliary materials • * * · »·· **» * «· ·· ***** * * Ι * * * * * * * * * * * * * t * «| This is to be deducted from the total residual moisture found in order to determine the residual moisture content from solvents. English:. * * * * * * * * *. By hot extrusion and thereby achieved mixing the liquefied or at least plasticized matrix with the active pharmaceutical ingredient and optionally other auxiliaries and / or additives, an intimate dispersion of the active pharmaceutical active ingredient is ensured with the matrix, at the same time adverse effects of solvents on the used Active ingredient can be avoided. Surprisingly, it has been found that such a matrix satisfies the above-mentioned objects of the present invention well. Although fatty acids have already been proposed as such in the prior art as constituents of retarding matrices, no reference can be found in the use of salts of such fatty acids as a retarding matrix in hot extrusion. In general, the free fatty acids differ considerably from their salts in terms of their physical properties, in particular with regard to melting point, boiling point and solubility. Stearic acid, for example, has a melting point of 69 ° C, while magnesium stearate has a melting point of about 140 ° C and calcium stearate has a melting point between 140 and 160 ° C. Saturated fatty acids as a subgroup of the alkanoic acids are fatty acids which have no double bonds between carbon atoms and form a homologous series with the empirical formula CnH 2miCOOH. Preferably, the pharmaceutically acceptable salts used in the invention are straight chain saturated fatty acids. In the oral retarding formulation, a variety of compounds can be used as an active pharmaceutical agent. Examples of useful agents include, but are not limited to, analgesics, anti-inflammatory agents, antihelminthics, antiarrhythmics, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, anticonvulsants, antifungals, anti-gout agents, antihypertensive agents, antimalarial agents , Antimigraine center !, Antimuscarinic, Antineoplastic, Anticancer, Center! for improving erectile dysfunction, immunosuppressants, antiprotozoics, antithyroid drugs, anxiolytics, sedatives, hypnotics, neuroleptics, beta-blockers, cardio-ionotropic agents, corticosteroids, diuretics, antiparkinson agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid-regulating agents, antipektangeal agents, antirheumatics, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional supplements, opioidanatgetics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, enhancers, anti-incontinence agents, nutritional oils, prostate therapeutics, essential fatty acids and non-essential fatty acids. The formulation may also comprise more than one active ingredient.

More specific examples of drugs include, but are not limited to, opioids, benzodiazepines, barbiturates, and stimulants, e.g. Methylphenidate and amphetamines, dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorvynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadone, benzphetamine, chiorendermine, diethylpropion, phentermine, mebutamate, chlortermin, phenyiacetone, benzphetamine, chloralhydrate, ethchlorvynol, paraldehyde , Midazolam and dextropropoxyphene.

In certain embodiments, at least one of the drugs may also be an opioid agonist. Useful opioid agonists include, but are not limited to, alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, decozin, diampromide, diamorphine, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate , Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophin, narcein, nicomorphine , Norlevorphanol, normethadone, nalorphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazine, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, propoxyphene, propylhexedrine , Sufentanil, tilidine, tramadol, pha Rmazeutisch acceptable salts thereof and mixtures of any two or more of the preceding. in certain embodiments, the opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, tapentadol, etorphine, dihydroetorphine, butorphanol , Levorphanol and mixtures thereof. In one embodiment, the opioid agonist is oxycodone, hydromorphone or hydrocodone.

It is particularly preferred if at least one of the active ingredients is nicomorphine, hydromorphone, codeine phosphate or naloxone or mixtures of any two or more of the foregoing.

The term "benzodiazepines" refers to benzodiazepine and drugs that are derivatives of benzodiazepines and are able to suppress the central nervous system.

Benzodiazepines include, but are not limited to, Alprazolam, Bromazepam, Chiordiazepoxide, Clorazepate, Diazepam, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Oxazepam, Prazepam, Quazepam, Temazepam, Triazolam, Methylphenidate, and mixtures of any two or more the preceded.

Barbiturates refer to sedative-hypnotic agents obtained from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbitai, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, and mixtures of two or more of the foregoing.

Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines, e.g. Amphetamine, dextroamphetamine resin complexes, dextroamphetamine, methamphetamine, methylphenidate, and mixtures of any two or more of the foregoing.

At least one of the active ingredients may be a substance to be released in the intestine, including, but not limited to, agents that act locally in the intestinal region to treat a bowel disease, e.g. irritable bowel syndrome, irritable bowel disease, Crohn's disease, constipation, postoperative atony, gastrointestinal infections, and therapeutic agents that deliver antigenic material into the lymphoid tissue. Agents for the treatment of intestinal diseases include, but are not limited to, 5-ASA; Steroids such as e.g. Hydrocortisone and budesonide; Laxative; Stool softeners; octreotide; cisapride; Anticholinerika; opioids; Calcium channel blocker, DNA for delivery to the cells of the intestine; glucosamine; Thromboxane A2 synthetase inhibitors such as e.g. ridogrel; 5HT3 antagonists, e.g. ondansetron; Antibodies to bacterial infections, e.g. Clostridium difficile and antiviral agents, e.g. for prophylaxis against HIV.

Alternatively, at least one of the active ingredients may be an agent that is systemically active and for which absorption in the intestinal region is improved. Such agents include polar compounds, e.g. Heparins, insulin, calcitonins; human growth hormone ("human growth hormone", HGH); Growth hormone releasing hormones (GHRH); Interferons, somatostatin and analogues such as e.g. Octreotide and vapreotide; Erythropoietin (EPO); Granulocyte intestinal stimulating factors ("granulocyte colony stimulating factor", GCSF); Parathyroid hormone (PTH); Luteinizing hormone releasing hormone (LHRH) and analogs thereof; atrial- 11 • »· atrial natriuretic factor (ANF); Vasopressin, desmopressin, calcitonin gene related peptides (CGRP) and analgesics. The drug matrix may further comprise hydrophobic materials, binders, plasticizers, adjuvants, and combinations of any two or more of the foregoing.

In one embodiment, the antidote is an opioid antagonist. Opioid antagonists useful in the present invention include, but are not limited to, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacin, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing. Useful opioid antagonist salts include salts formed from an acid and the basic nitrogen groups of the opioid antagonist. Examples of opioid antagonist salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, Bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and palmoate (ie, 1,1'-methylenebis (2-hydroxy -3-naphthoate)) - salts.

Other opioid antagonist salts include salts prepared from an antagonist having an acid functional group such as a carboxylic acid group or a sulfonic acid functional group and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, those mentioned in the paragraph which is termed " pharmaceutically acceptable salt " are designated.

In certain embodiments, the opioid antagonist is nalmefene, naloxone, naltrexone or a pharmaceutically acceptable salt thereof. In a further embodiment, the opioid antagonist is a naltrexone salt, e.g. Naltrexone hydrochloride.

Benzodiazepine antagonists which may be used as antidotes in the present invention include, but are not limited to, flumazenil.

Barbiturate antagonists which may be used as antidotes in the present invention include, but are not limited to, amphetamines described herein. 12 • I • * # ·· »·» «·»

Stimulant antagonists that may be used as antidotes in the present invention include, but are not limited to, benzodiazepines as described herein.

In a further embodiment of the present invention, the antidote is an agent which causes an unpleasant physiological reaction, such as hypotension. Nausea causes. This type of antidote may be used with any type of therapeutic agent including an opioid, a benzodiazepine, a barbiturate or a stimulant. Examples of emetics suitable for use as an antidote in the present invention include any agent that will safely and effectively induce vomiting following administration, including but not limited to ipecacuanha and apomorphine.

According to a preferred embodiment of the present invention, the retarding matrix is based on a pharmaceutically acceptable metal salt of a saturated fatty acid having 10-26, preferably 10-20 C atoms, more preferably a pharmaceutically acceptable salt of a metal of group 2 of the periodic table with stearic acid, in particular Calcium stearate and / or magnesium stearate. Calcium stearate, for example, is currently used in the manufacture of so-called non-tox stabilizers of plastics, and is also used as a lubricant in pharmaceutical products and as a lubricant in the paper and metal processing industry and in sand processing. Because of its use in pharmaceutical products, there is no question that calcium stearate is pharmaceutically acceptable. Magnesium stearate is also already in use in the pharmaceutical industry, it is used, for example, as an aid for tablet or granule production or in some sweets.

Preferably, the retarding matrix is prepared by melt extrusion, wherein optionally in the retarding matrix at least one plasticizer or plasticizer, the two terms are considered to be synonymous with each other, may be incorporated, which is preferably selected according to the invention from the group comprising citrate esters, fatty acid esters, sebacic acid esters , Phthalic acid esters and glycol derivatives and mixtures thereof, more preferably tributyl citrate and / or glycerol monostearate. It has been found that when incorporating plasticizers as a functional additive, the release from the retarding matrix used according to the invention is readily controllable, the release of the active ingredient depending on the concentration of the plasticizer used. It should be noted, however, that the matrix of the present invention is based on a pharmaceutically acceptable salt of a saturated fatty acid of 10-26, preferably 10-20 *. *.

······· 13 C atoms is also retarding effective without admixture or incorporation of a plasticizer.

According to a preferred embodiment of the present invention, the plasticizer (s) are incorporated into the matrix in an amount of between 1 and 50% by mass, more preferably in an amount of between 5 and 15% by weight, based on the total weight of the formulation. Using the most preferred amount, there is an optimal balance between processing of the raw material and control of the release of the active pharmaceutical agent. It is also advantageous if the active pharmaceutical active ingredient is incorporated in the matrix in a loading of up to 90% by weight, but preferably of up to 50% by weight, based on the total mass of the formulation. The loading of active pharmaceutical agent will depend on the intended dosage as well as the intended release time and may vary within a wide range. According to the invention, the release rate can be controlled in a controlled manner by the extent of loading with the pharmaceutical active substance.

According to the invention, it is also provided that the formulation is in the form of pellets or cylinders having an average diameter of preferably between 0.5 and 5 mm and more preferably between 0.5 and 2 mm. Such a formulation can be easily filled into capsules, compression to tablets is also possible.

According to a preferred embodiment, the present invention also relates to a method for the preparation of a formulation as described above, wherein the retarding matrix is formed by hot extrusion of a mixture of matrix former, active pharmaceutical agent and optionally plasticizer in an extruder and subsequent head knock to form pellets becomes. Preferably, in such a method, a co-rotating twin-screw extruder is used, as it is known in the prior art and has also been described in the introduction of the present invention.

In itself, the hot extrusion can be carried out in a temperature range of 50 to 200 ° C, preferably in a temperature range of 90 to 130 ° C, more preferably between 110 and 130 ° C. It goes without saying that the selected temperature range of the choice of the matrix former for the retarding matrix and

»* Μ Ι Μ» »fl fl I I I I I · · · · · · · · · · · · · · · · · · · · · ·. It will also depend on the choice of other plasticisers or optional adjuvants and / or additives chosen, as well as not least on the particular active pharmaceutical active ingredient. In any case, the temperature used in the hot extrusion will be below the melting temperature of the matrix former used, since further energy is introduced into the mixture by the extrusion. It is the knowledge of a person skilled in the art to select suitable pairings of matrix formers and active pharmaceutical active ingredients, wherein the active pharmaceutical active substance may not be thermally damaged by the liquefaction or plasticizing of the matrix former and the melting temperature of the matrix former is high enough to the finished formulation to give thermal stability.

The present invention will be explained in more detail below with reference to a few concrete exemplary embodiments, to which, however, it is not restricted.

In the development of formulations according to the invention based on a novel matrix system of a pharmaceutically acceptable salt of a saturated fatty acid having 10-26, preferably 10-20 carbon atoms, the following questions have been defined and systematically investigated: Is such a salt as matrix base (optionally in combination with plasticizers) extrudable and debatable? • In which concentration can the active pharmaceutical active ingredient (possibly in the form of a model drug) be incorporated? • Are the pellets releasing the model drug retarded? • Is there a relationship between particle size, loading concentration and release behavior? • Are there incompatibilities between the salt as a matrix base and the drugs listed? • Soft modifications (amorphous or crystalline) take the salt as a matrix base before, during and after the process?

Does the choice of plasticizer influence the release profile? II M MM »Ml * Ι ·

• • »« I 4 4 II »· I 4 4- * * 4« 4 «· 4 · ♦ *« * 4 + 1 444 4 «4 4 4 4 44 · 4 4 ·» «4 44 15 For examinations The formulations were used as the matrix system vegetable calcium stearate (CaSt, WerbaChem, AT), and, for the evaluation of drug release, the model drug paracetamol (GL Pharma, AT) incorporated into the formulations. As softening agent, tributyl citrate (TBC, G.L. Pharma, AT) was added to the formulations at a concentration of 10% and 5%, respectively. To evaluate the influence of the plasticizer, further studies were carried out with glycero monostearate (5%).

Toxicology Calcium stearate: LD / LC50 values relevant for classification: oral LD50> 10000 mg / kg (rat); no primary irritant effect, on the skin: no irritant effect, on the eye: irritant effect, sensitization: no sensitizing effect known. The substance is not subject to classification according to the EC lists in the latest version.

Method: 1. CaSt was at pre-examination without AP! extruded to determine the screw configuration or the optimum process temperature (with and without the addition of the plasticizer tributyl citrate (10%)) using the Coperion ZSK 18 brand extruder used. It worked with nozzle diameters of 1.5 mm and 1.0 mm. Since the Extrudatstrange had no stickiness, could be dispensed with the incorporation of an anti-tacking component. The pellet deduction was made by hot-head discount. 2. In parallel to the extrusion experiments, the preferred active ingredients (i.e., nicomorphine HCl, naloxone HCl, hydromorphone HCl or codeine phosphate), the matrix former and the respective mixtures were examined for their Tm, Tg and Tdeg. The modification and compatibility studies were performed by SWAXS / DSC / HPLC measurements. 3. Subsequently, the excipients used (i.e., CaSt in combination with tributyl citrate 10% and 5%, respectively) were loaded with various amounts of a model drug, namely 20% and 40% paracetamol. 4. In addition, the influence of the plasticizer on the process and in vitro drug release was evaluated. For this purpose, TBC was replaced by glycero monostearate (GMS) and incorporated in a concentration of 5% in the CaSt / paracetamol (5, 10, 20 and 40%) matrix. 5. The melt-extruded formulations were prepared according to the USP / Paddle method, Apparatus 2 or USP / Basket method, Apparatus 1 (agitation: 100 or 50 rpm, 9 9 99 x < ** x "x" 99 x «·« 9 «· 9 · ·« # '9 · »f« «·« * «' 1 · 9 * ♦ ♦ · · · f * 9 99 · 9 * ·· 99 9 · 99 16

Temperature: 37 ± 0.5 ° C, n = 6. Sampling (1 ml) after 10, 30, 60 minutes, subsequently at 2, 3, 4, 5, 6, 7, 8 and 24 hours). 0.1N HCl (pH 1.2) and 0.2M trisphosphate dodecahydrate buffer (pH 6.8) were used as the release media. The samples were subsequently analyzed by HPLC.

Results: 1. Extrusion / hot break

The results showed that extrusion of CaSt in combination with 10% TBC is possible. The necessary process temperature was between 90-110 ° C, accordingly, the drug is embedded as a solid dispersion or solution in the matrix. Both the 1.0 mm and 1.5 mm dies could be used for the extrusion. The screw configuration is shown in Fig.2.

The pellets were made by cutting the extrudate strands with a head knock, sieved and grit sizes of 1.0 mm and 1.5 mm respectively (according to the nozzles used) for further investigations. 2. In vitro studies:

The release studies were carried out according to the USP in HCI / phosphate buffer (simulation of the stomach or intestinal milieu). The results showed that the drug slows down paracetamol, i. retarded from the CaSt / TBC matrix pellets was released. The release concentrations changed depending on the incorporated drug concentration and pellet size. As the pellet size increased, the surface area decreased, releasing the drug more slowly. The higher the loaded drug concentration, the faster the drug release occurred.

At a drug loading of 20% and the addition of the plasticizer TBC in an amount of 10%, the paracetamol concentration measured after 8 hours for 1.0 mm pellets was 65.62% and 57.47%, respectively. Pellets with a particle size range of 1.5 mm showed a slowdown in drug release due to the reduced surface area.

In Fig. 3, release profiles of CaSt 70% / TBC 10% / paracetamol 20% pellets are shown, namely: ······· * ··· · · ι

B · t ft · B »B • · · · · · · · * · 9 · 9 · B * B Bll

BBBB «« 9 B • BB BB BB BB «I 9« 17 A) 1.0 mm pellets, the released paracetamol concentration after 8 hours was 65.62% B) 1.0 mm pellets, the released paracetamol concentration after 24 Hours was 80.10% C) 1.5 mm pellets, the released acetaminophen concentration after 8 hours was 57.47% D) 1.5 mm pellets, the released acetaminophen concentration after 24 hours was 73.82%

The results of the pellets with 40% drug loading and a TBC concentration of 10% show a retarding release profile. Figure 4 shows the release profiles of CaSt 50% / TBC 10% / paracetamol 40% pellets, namely: A) 1.0 mm pellets, 100% drug release after 6 hours B) 1.5 mm pellets, 100% drug release after 8 hours C) 1.0 mm pellets, 100% drug release after 24 hours D) 1.5 mm pellets, 100% drug release after 24 hours

For the 1.0mm pellets, complete drug release was observed after only 6 hours. For the 1.5mm pellets, all of the drug was released after 7 hours.

By incorporating 5% plasticizer (TBC) into the formulation with CS and 20% paracetamol, 67.57% and 34.55% paracetamol, respectively, were detected by HPLC after 8 hours of release. Larger particles again showed a decrease in the released drug concentration. Fig.5 shows 5% / paracetamol 20% pellets, namely: the release profiles of CaSt 75% / TBC A) 1.0 mm pellets, after paracetamol concentration 67.57% 8 hours was the liberated B) 1.5 mm pellets , after paracetamol concentration 34.55% 8 hours was the released

«* ·· * * · I * · * ·« ··································································································································································································· Pellets, after paracetamol concentration 99.50% 24 hours was the released D) 1.5 mm pellets, after Paracetamoikonzentration 67.07% 24 hours was released

In addition, loading studies with a drug concentration of 40% with the addition of 5% plasticizer (TBC) were performed in order to evaluate the influence of the concentration of the plasticizer on the drug release. After conducting the in vitro releases, the drug concentration of the 1.0 mm pellets measured after 8 hours was 78.87% and the 1.5 mm pellets were 62.22%. Fig.6 shows the release profiles of CaSt 55% / TBC 5% / paracetamol 40% pellets, namely: A) 1.0 mm pellets, the released acetaminophen concentration after 8 hours was 78.87% B) 1.5 mm large Pellets, the released paracetamol concentration after 8 hours was 62.22% C) 1.0 mm pellets, the released paracetamol concentration after 24 hours was 103.27% D) 1.5 mm pellets, the released acetaminophen concentration after 24 hours was 92.94%

The decrease in the amount of active ingredient released can be attributed to the resulting increased amount of CaSt. Thus it can be stated that CaSt can be extruded on and out on the one hand with low plasticizer concentrations, on the other hand the release pro! can be varied by the concentration of the plasticizer. In further studies, the plasticizer TBC was replaced with GMS. The dissolution studies with GMS as a plasticizer showed differences in drug release. By incorporation of 5% GMS in CaSt / acetaminophen (5%) mixtures, only 20.56% and 15.14% of the active ingredient in the release medium were detected after 8 hours of release of the matrix pellets. Again, it was shown that with a larger pellet diameter, the released drug concentration decreased, Fig.7 shows the release profiles of CaSt 90% / GMS 5% / paracetamol 5% pellets, namely:

19 • * φφφφφφφφφ ··· · * · * * * • φ φ · φ «··· * φ φ * * ♦ φ · φ» * φ · φ ♦ »· φ φ φ • * # · # φφφ φ · Α) 1.0 mm pellets, the released paracetamol concentration after 8 hours was 20.56% B) 1.5 mm pellets, the released acetaminophen concentration after 8 hours was 15.14% C) 1.0 mm large Pellets, the released paracetamol concentration after 24 hours was 26.51% D) 1.5 mm pellets, the released acetaminophen concentration after 24 hours was 19.80%

Furthermore, the drug loading with paracetamol was increased to 20%. Fig. 8 shows the release profiles of the CaSt75% / GMS5% / paracetamol20% pellets, namely: A) 1.0 mm pellets, the released paracetamol concentration after 8 hours was 31.57% B) 1.5 mm pellets, the released paracetamol concentration after 8 hours was 23.05% C) 1.0 mm pellets, the released acetaminophen concentration after 24 hours was 47.52% D) 1.5 mm pellets, the released paracetamol concentration after 24 hours was 32 , 53%

Again, it could be shown that the released concentration of paracetamol decreased with larger pellet diameter.

In further studies, the loading of paracetamol was increased to 40%. Fig. 9 shows the release profiles of the CaSt55% / GMS5% / paracetamol40% pellets, 1.5 mm, namely: A) after 8 hours the released drug concentration was 33.36% B) after 24 hours the released drug concentration was 49.61%

The concentrations determined after 8 hours were 33.36% for the 1.5 mm pellets.

The results show that drug loading (i.e., 5-40%) has little effect on the rate of release when using GMS as a plasticizer. 3. Characterizations:

incompatibilities

In the case of CaSt, no incompatibilities with naloxone HCl, nicomorphine HCl or hydromorphone HCl were found. By means of the DSC (differential scanning calorimetry), thermal transformations of an active ingredient / excipient can be detected. This method is based on the detection of the amount of heat released / required during the chemical and / or physical conversion. For these tests, the CaSt / API mixtures were heated to 140 and 170 ° C (heating rate: 5K / min) and again cooled to 35 ° C (cooling rate: 10K / min). The obtained samples were analyzed by HPLC. The resulting chromatograms, shown as Fig. 10, showed no degradation products in all formulations.

modification studies

Studies in pharmaceutical analysis show that the SAXS / SWAXS method can be used as standard analysis in the pharmaceutical laboratory. By means of point-focused X-ray optics with increased resolution, molecular structures can be specified more precisely and used directly for quality assessment. By combining small-field and wide-angle X-ray scattering (SAXS / SWAXS) with a Differential Scanning Calorimeter (DSC), phase transitions and reactions in powders or melts can be studied simultaneously in a single experiment.

CaSt

The SWAXS / DSC measurements of pure CaSt showed that 2 transitions occurred in the thermogram before melting. Upon cooling, the crystal lattice expanded and recrystallization of the matrix system occurred at 95 ° C. The results of the recrystallization of pure CaSt in the cooling scan between 163 - 67SC are shown in Fig.11.

In summary, the examinations made allow the following conclusion: ···· * · · · t * I * »· ♦ * *» · t «· * * · · * · · *** · I t * ··« · "• The extrudability as well as the heat deflection of calcium stearate in combination with TBC is given, the use of solvents can be dispensed with. • The incorporation of a model drug (paracetamol) is possible up to 40%. »A delayed release profile could be achieved. • There is a relationship between particle size, loading concentration and release behavior. As the particle size increases, the released drug concentration decreases; As drug loading increases, drug release increases. • There are no incompatibilities with the tested drugs.

Based on the results obtained, formulations were prepared with the preferred active pharmaceutical active ingredients hydromorphone HCl and another opioid (codeine phosphate), as well as nicomorphine HCl.

Materials Test Formulations: Again, CaSt (WerbaChem) was used as the matrix system for testing the test formulations. Codeine phosphate (10%) and hydromorphone HCl (10%) were incorporated into the formulations on the one hand as drugs. This drug concentration has already been chosen with regard to the final product. As a plasticizer tributyl citrate was added for the test formulations in a concentration of 10% and 5%.

Methodology Test Formulation: 1. CaSt was mixed with the respective drugs and delivered to the extruder by dosing system. Tributyl citrate (10% and 5%, respectively) was added by means of an HPLC pump. It was worked with a nozzle diameter of 1.0 mm (in terms of the final product). Since the extrudate strands had no stickiness, the incorporation of an anti-tacking component could also be dispensed with here. The pellet impact was made by hot head-off, with all formulations external cooling air supply was required (reduced plasticity of the active ingredients). • * * »#» · suffered · Μ •••••••••••••••••••••••••••••••••••••••••••••• •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• · 4 * * ·· ftftft · · * 22 2. The melt-extruded test formulations [ie 10 mg API / g!) Were prepared according to the USP / Paddle method, Apparatus 2 or USP / Basket method, Apparatus 1 (agitation: 100 or 50 rpm, temperature: 37 ± 0.5 ° C, n = 6) (1 mi) after 10, 30, 60 minutes, subsequently after 2, 3, 4, 5, 6, 7, 8 and 24 hours). 0.1N HCl (pH 1.2) and 0.2M trisphosphate dodecahydrate buffer (pH 6.8) were used as the release media. The samples were subsequently analyzed by HPLC.

Results Test Formulations: 1. Extrusion / hot break

The screw configuration as shown schematically in Fig. 2 could be retained.

The results of the examined matrix carrier showed that extrusion of CaSt (in combination with 10% and 5% TBC, respectively) was possible by incorporation of both active ingredients. The necessary process temperature was between 110-130 ° C, accordingly, the drug (s) embedded in the test formulation also exist as solid dispersion in the matrix. The pellets were prepared by cutting the extrudate strands with a head knock, sieved and using grain sizes of 0.8-1.0 mm (according to the nozzle used - for the final product) for further investigation. 2. In vitro release

Hydromorphone HCl:

The dissolution studies were conducted under the same conditions (i.e., according to the USP) because there is no specific protocol for retarding hydromorphone preparations in the pharmacopoeia. Fig. 12 shows the release profiles of CaSt 80% / TBC 10% / HydromorphoneHCi 10% pellets, 1.0 mm, namely: A) the released hydromorphone concentration after 8 hours was 75.18% B) the released hydromorphone concentration was after 24 hours at 92.32%

The results show a sustained release profile of the hydromorphone formulations; after 8 hours, 75.18% of the drug was detected in the release medium, after 24 hours 92.32%. 23 • ·· · · * ·· »

Based on the results obtained, the influence of the plasticizer concentration on the release behavior of hydromorphone HCl was investigated. For this purpose, the amount of TBC used was reduced to 5%. The process temperature was again between 110-130 ° C. Fig. 13 shows the release profiles of the CaSt85% / TBC 5% / HydromorphoneHCl 10% pellets, namely: A) the released hydromorphone concentration after 8 hours was 75.17% B) the released hydromorphone concentration after 24 hours was 107.86% ( ± SD)

The kink, which can be seen between 2 and 3 hours in the release profile, is due to the pH change from 1.2 to 6.8.

The results show that by lowering the TBC concentration or increasing the CaSt content by 5%, the active ingredient hydromorphone HCl diffuses more slowly from the pellets until the 6th hour. The concentrations measured after 8 and 24 hours were in both formulations, i. regardless of the TBC concentration, at 75 and 95-100%, respectively. Accordingly, it should be noted that the release of the active ingredient is controllable by the plasticizer concentration.

codeine:

The results of the release studies with codeine phosphate show that after 8 hours 66.12% or after 24 hours 96.89% of the API used were released. Fig. 14 shows the release profiles of the CaSt85% / TBC5% / codeine phosphate 10% pellets, namely: A) the released codeine concentration after 8 hours was 69.54% B) the released codeine concentration after 24 hours was 96.89%

The kink, which can be seen between 2 and 3 hours in the release profile, is due to the pH change from 1.2 to 6.8.

The codeine phosphate formulations were previously extruded with the addition of 5% TBC, the results are comparable to those of hydromorphone HCl.

In summary, based on the above investigations: * The extrudability and the hot break of calcium stearate in combination with TBC and the active ingredients Hydromorphone HCi and codeine phosphate is given, the use of solvents can be omitted. * A delayed release profile could be achieved. * If necessary, formulation changes can be made by the concentration of TBC,

Test formulations with nicomorphine HCl

For this purpose, the following questions were defined and systematically investigated: * Is the extrudability or the knock-off capability also given for the incorporation of nicomorphine HCl? * Can a retarded drug profile be achieved? * Are formulation changes needed?

Materials Test Formulations: In this case too, CaSt was used as the matrix system for the investigations of the test formulations. Nicomorphine HCl was incorporated at a concentration of 25% in the formulation. As plasticizer tributyl citrate was again added in a concentration of 10% and 5%.

Method Test Formulation: 1. CaSt was mixed with nicomorphine HCl and fed into the extruder via a dosing system. Tributyl citrate {10% and 5%, respectively) was added by means of an HPLC pump and the molten mixture was extruded through a 1.0 mm die (for the final product). Since the extrudate strands had no stickiness, the incorporation of an anti-tacking component could also be dispensed with here. The pellet impact was made by hot head-off, with all formulations external cooling air supply was required (reduced plasticity of the active ingredients). 2. The melt-extruded test formulations [ie100 mg API] calculated on the determined capsule volume) were prepared according to the USP / Paddle method, Apparatus 2 or USP / Basket method, Apparatus 1 (agitation: 100 or 50 rpm, temperature: 37 ± 0.5 ° C, n = 6.

Sampling (1 ml) after 10, 30, 60 minutes, subsequently at 2, 3, 4, 5, 6, 7, 8 and 24 hours). 0.1N HCl (pH 1.2) and 0.2M trisphosphate dodecahydrate buffer (pH 6.8) were used as the release media. The samples were subsequently analyzed by HPLC.

Results Test Formulation: 1. Extrusion / Hot Tear

The screw configuration as shown in Fig.2 could be retained.

It has been shown that the extrusion and, subsequently, the hot peel were possible with the formulations of CaSt in combination with the plasticizer TBC (10% or 5%) and 25% nicomorphine. The necessary process temperatures were between 90-130 ° C; Consequently, the formulation with the Nicomorphine HCl API is also present as a solid dispersion in the CaSt matrix used. For the further experiments, the pellets produced were sieved and the fraction of 0.8-1.0 mm was used. 2. In vitro release

Since there is no specific pharmacopoeial protocol for the release studies of retarding nicomorphine HCl preparations, the dissolution studies were performed according to the general USP (i.e., HCl / phosphate buffer) regulations. The investigated formulation with the addition of 5% TBC shows a sustained release profile. After 8 hours, 63.29% nicomorphine HCl was detected in the release medium by HPLC. The 24 hour API concentration increased to 64.39% (Fig.16). The higher concentration of TBC is expected to increase the release profile. Fig. 15 shows the release profiles of the CaSt70% / TBC5% / NicomorphinHCI25% pellets, namely: A) After 8 hours, the released nicomorphine HCl concentration was 38.73% B). After 24 hours, the released nicomorphine HCl concentration was 52.57 %

In the release profile, a kink is recognizable between the 2nd and the 3rd hour, which is due to the pH change from pH 1.2 to pH 6.8.

Fig.16 shows the release profiles of the CaSt65% / TBC10% / NicomorphinHCI25% pellets, namely: * »at i« t »· · · ·» · * «· · • ♦ 26 • * · * · ·· · * · i · * * ·· A) after 8 hours the released nicomorphine HCl concentration was 63,29% B) after 24 hours the released nicomorphine HCl concentration was 64,39%

In the release profile, a kink is recognizable between the 2nd and the 3rd hour, which is due to the pH change from pH 1.2 to pH 6.8.

In summary, the following can be stated: • The extrudability and the hot rebound of calcium stearate in combination with TBC and the active ingredient nicomorphine HCl is given, the use of solvents can be dispensed with. • A retarded release profile could be achieved. • an increase in the released API concentration is to be expected.

As a comparison originator studies were carried out with the drug Hydal®retard. The following requirements have been defined: • The release behavior of the Hydal®retard capsules 8mg or Hydai®retard capsules 4mg (Mundipharma) is investigated. • The release studies are carried out by paddle and basket method.

Materials Originator Investigations: Hydal @ retard capsules 8mg (Mundipharma) were used for the initial examinations of the original preparation.

Methodology Originator Investigations:

The release studies of the originator were performed in 0.1 N HCl and 0.2 M trisodium phosphate dodecahydrate buffer. To evaluate the appropriate dissolution methodology, one capsule / vessel was released according to the paddle method and the basket method according to the USP (agitation 100 rpm, temperature of 37 ± 0.5 ° C., 6-fold determination). Sampling (1 ml) was carried out after 10, 30 minutes and in further consequence after 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours. The analysis of the samples was carried out by HPLC.

Results Originator Investigations 1. In vitro release

Since both the originator capsule and the originator pellets swayed in the dissolution medium, both pharmacopoeias were used to determine the dissolution profile.

Paddle method:

The results show that the active ingredient Hydromorphone HCl released from the capsule was released. In the investigations carried out using the paddle method (agitation of 100rpm) were released after 8 hours 91.90% of the active ingredient contained in the capsule. After a period of 24 hours, there was a complete release of the contained hydromorphone from the drug form. Fig.17 shows the release profile of the Hydal®retard 8mg capsules using the paddle method (100rpm), namely: A) the released hydromorphone concentration was 91.90% after 8 hours B) the released hydromorphone concentration was 101.12 after 24 hours % (± SD)

Summary

A comparison between Originator Hydal®retard and CaSt / TBC / Hydromorphone HCl Pellets 1.0 mm showed that both formulations show a similar release profile. Figure 18 shows a comparison of the release profiles using the paddle method (100rpm), namely: A) 8 hours comparison, B) 24 hours comparison

Determination of the residual moisture of hot-extruded CaSt pellets according to the invention

The residual moisture of the pellet formulations according to the invention prepared by hot extrusion with CaSt as matrix system was determined by means of thermobalance. Paracetamol (P), nicomorphine HCl (NM), codeine (C) and hydromorphone (HM) were used as active pharmaceutical active ingredients. The functional additives on the one hand were the liquid plasticizer tributyl citrate (TBC) and on the other hand the solid plasticizer glycerol monostearate (GMS) Incorporated formulation. For the pellets produced with the 1.0 mm die (referred to as "1.0" in the table below), the target fraction was between 1.0 and 1.25 mm diameter, when extruded with the 1.5 mm die (referred to in the following table as "1.5") the target fraction was between 1.4 and 1.6 mm in diameter.

Formulation Residual moisture r% -Massel CaSt100% 1.0 0.297 CaStl 00% 1.5 0.387 CaSt80% / P20% 1.0 0.393 CaSt80% / P20% 1.5 0.307 CaSt75% / TBC5% / P20% 1.0 0.283 CaSt75% / TBC5% / P20% 1.5 0.277 CaSt70 % / TBC10% / P20% 1.0 0.390 CaSt70% / TBC10% / P20% 1.5 0.377 CaSt75% / GMS5% / P20% 1.0 0.377 CaSt75% / GMS5% / P20% 1.5 0.390 Ca St 70% / TB C 5% / N M2 5% 1.0 0.513 CaSt65% / TBC10% / NM25% 1.0 0.387 CaSt85% / TBC5% / Cl 0% 1.0 0.380 CaSt85% / TBC5% / HM10% 1.0 0.390 CaSt80% / TBC10% / HM10% 1.0 0.580 CaSt70% / TBC20% / HMl 0% 1.0 0.763

Claims (14)

  1. • a · a · a · a a a * · < Claims 1. An oral retarding formulation containing at least one retarding matrix with at least one active pharmaceutical active compound mixed with this matrix, characterized in that the retarding matrix on a hot-extrudable pharmaceutically acceptable salt of a saturated Fatty acid having 10-20 carbon atoms and containing less than 1.0% by weight, more preferably less than 0.6% by weight, based on the total weight of the formulation, of residual moisture content of solvents.
  2. Formulation according to claim 1, characterized in that the retarding matrix is based on a pharmaceutically acceptable metal salt of saturated fatty acids of 10-20 carbon atoms.
  3. 3. Formulation according to one of claims 1 or 2, characterized in that the retarding matrix is based on a pharmaceutically acceptable salt of a metal of group 2 of the periodic table with a saturated fatty acids having 10-20 carbon atoms.
  4. 4. A formulation according to any one of claims 1 to 3, characterized in that the retarding matrix is based on a pharmaceutically acceptable salt of a metal of group 2 of the periodic table with stearic acid.
  5. 5. Formulation according to claim 4, characterized in that the retarding matrix is based on calcium stearate and / or magnesium stearate.
  6. 6. A formulation according to any one of claims 1 to 5, characterized in that the retarding matrix was prepared by melt extrusion.
  7. 7. Formulation according to one of claims 1 to 6, characterized in that in the retarding matrix at least one plasticizer is incorporated.
  8. 8. A formulation according to claim 7, characterized in that the one or more plasticizers is / are selected from the group comprising citrate esters, fatty acid esters, sebacic acid esters, phthalic acid esters and glycol derivatives. «Ft 4 • 4 * 4 4 · 0 * t« 4 «44» · «30
  9. 9. Formulation according to claim 8, characterized in that the plasticizer (s) is tributyl citrate and / or glycerol monostearate.
  10. 10. A formulation according to any one of claims 7 to 9, characterized in that the one or more plasticizers in an amount of between 1 and 50% by weight, particularly preferably in an amount between 5 and 15% by weight, based on the total mass of the formulation , are incorporated into the matrix.
  11. 11. A formulation according to any one of claims 1 to 10, characterized in that the active pharmaceutical active ingredient in a loading of up to 50% by weight, based on the total mass of the formulation, is incorporated into the matrix.
  12. 12. A formulation according to any one of claims 1 to 11, characterized in that the formulation is in the form of pellets or cylinders having an average diameter of preferably between 0.5 and 2 mm.
  13. 13. A process for the preparation of a formulation according to any one of claims 1 to 12, characterized in that the retarding matrix is formed by melt extrusion of a mixture of matrix former, active pharmaceutical agent and optionally plasticizer in an extruder and subsequent head knock to form pellets or cylinders ,
  14. 14. The method according to claim 13, characterized in that the melt extrusion in a temperature range of 90 to 130 aC, more preferably between 110 and 130 ° C is performed.
AT7722011A 2011-05-26 2011-05-26 Oral retardant formulation AT511581A1 (en)

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