WO2015165821A1 - Procédé et dispositif pour la fabrication d'une composition pharmaceutique - Google Patents

Procédé et dispositif pour la fabrication d'une composition pharmaceutique Download PDF

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Publication number
WO2015165821A1
WO2015165821A1 PCT/EP2015/058947 EP2015058947W WO2015165821A1 WO 2015165821 A1 WO2015165821 A1 WO 2015165821A1 EP 2015058947 W EP2015058947 W EP 2015058947W WO 2015165821 A1 WO2015165821 A1 WO 2015165821A1
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WO
WIPO (PCT)
Prior art keywords
weight
extrusion
extruder
extrudate
implant
Prior art date
Application number
PCT/EP2015/058947
Other languages
German (de)
English (en)
Inventor
Murad RUMMAN
Marco Spitz
Motokazu DOHI
Original Assignee
Acino Supply Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Acino Supply Ag filed Critical Acino Supply Ag
Priority to EP15718486.2A priority Critical patent/EP3137061A1/fr
Priority to CN201580030280.3A priority patent/CN106413689A/zh
Publication of WO2015165821A1 publication Critical patent/WO2015165821A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH] (Somatotropin)
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to the production of pharmaceutical compositions by extrusion.
  • the product quality can be increased and a reduction of the costs can be achieved.
  • biodegradable implants There are various methods for producing biodegradable implants. Starting from a homogeneous mixture of active ingredient and the corresponding polymers which control drug release, this mixture is administered i.d.R. processed by extrusion. Various techniques can be used for this, e.g. Screw extrusion or piston extrusion.
  • the mixture is thereby heated and melted and the melt is pressed by means of a nozzle into a strand of defined diameter.
  • the extrusion force increases again because the melt is forced to change the flow direction radially towards the extrusion die.
  • Viscosity fluctuations can also result in rare cases from slightly different properties of different batches of polymer used (in particular with regard to the molecular weight) and the active ingredient used.
  • the extrusion force is subject to continuous slight variations.
  • the prior art is mostly a two-step process of first forming a strand which is cut after a certain time, followed by actually cutting the strand into implants of defined active content.
  • the patent application EP 0 858 323 A1 (from WO98 / 09613) describes in Example 1 a process for the production of implants using a screw extruder from. Brabender (Duisburg, Germany) and a cutter of the Fa. Davis standard (Cedar Grove, NJ , USA). This method has the disadvantage that it is very time consuming because it involves two separate processes. Also, since these processes often have a manual component, there is a risk that product quality suffers.
  • the object underlying the invention is therefore achieved by a process for preparing a pharmaceutical composition in which a mixture containing at least one active ingredient and at least one pharmaceutically acceptable excipient is extruded by means of an extrusion device, and the resulting extrudate is cut, whereby the pharmaceutical composition is formed, characterized in that the pharmaceutical composition is weighed, and in the case that the weight of the pharmaceutical composition is outside a predetermined range, at least one parameter of the extrusion device, which has an effect on the weight of the pharmaceutical compositions to be produced, is changed so that subsequently produced pharmaceutical compositions have a weight which is within the predetermined range.
  • the inventors have succeeded in controlling the cutting process in combination with on-line control weighing so that the amount of compositions produced, e.g. Implants weighing outside the specified limits, i. of the acceptable fluctuation range, e.g. +/- 5 wt .-% could be reduced by over 90% and the standard deviation or relative standard deviation of the individual masses produced by more than 50% could be reduced, so that the product quality could be significantly improved by this measure (the numbers refer to the standard deviation on the entirety of the implants produced, ie without taking into account the subsequent sorting out of implants outside the desired specification, as well as on that implant bundle in which implants outside the desired specification have already been sorted out).
  • the numbers refer to the standard deviation on the entirety of the implants produced, ie without taking into account the subsequent sorting out of implants outside the desired specification, as well as on that implant bundle in which implants outside the desired specification have already been sorted out).
  • the invention relates to a process for the preparation of a pharmaceutical composition, such as an implant, in which a mixture containing (i) oxytocin or a pharmaceutically acceptable salt or derivative thereof and (ii) at least one pharmaceutically acceptable excipient, is extruded by means of an extrusion apparatus, and the resulting extrudate is cut, whereby the pharmaceutical composition is produced, characterized in that the pharmaceutical composition is weighed, and in the case that the weight of the pharmaceutical composition is outside a predetermined range, at least one parameter of Extrusion device, which affects the weight of the pharmaceutical compositions to be produced, is changed so that subsequently produced pharmaceutical compositions have a weight which is within the predetermined range.
  • the method according to the invention thus enables the preparation of a collective of pharmaceutical compositions, such as implants, containing an active substance, such as oxytocin or a pharmaceutically acceptable salt or derivative thereof, which has a weight distribution with a relative standard deviation of 0.1-3%, typically 0.5. 2%. Furthermore, the method according to the invention enables the production of a collective of pharmaceutical compositions, eg implants, containing an active ingredient, eg. Oxytocin or a pharmaceutically acceptable salt or derivative thereof, said compositions preferably having a weight distribution such that more than 90%, preferably more than 95%, in particular more than 99% of the compositions have a weight of at most 5% of the target weight .-% deviates.
  • the mixture is a powder mixture, a granulate or another meltable composition containing the active ingredient (eg oxytocin or a pharmaceutically acceptable salt or derivative thereof) and at least one pharmaceutically acceptable excipient. If necessary, the mixture may contain one or more other active ingredients.
  • the active ingredient eg oxytocin or a pharmaceutically acceptable salt or derivative thereof
  • the mixture may contain one or more other active ingredients.
  • the pharmaceutical composition containing the active ingredient (eg oxytocin or a pharmaceutically acceptable salt or derivative thereof), and optionally one or more other active ingredients, as well as at least one pharmaceutically acceptable excipient according to the present invention is a solid or semi-solid pharmaceutical composition, preferably an implant.
  • Implants are implantable drug depots that release an active ingredient over a prolonged period of time (e.g., for at least one month) and can therefore be used for the long-term treatment of diseases.
  • the "predetermined range” or “predetermined weight range” is the weight range of the pharmaceutical composition outside which there is a readjustment (ie a change in at least one parameter of the extrusion device which affects the weight of the pharmaceutical compositions to be produced).
  • the desired target weight of the pharmaceutical composition is always within the prescribed range.
  • the "acceptable range of variation" is the weight range within which the pharmaceutical composition must be in order to be acceptable for further use and, where appropriate, processing If the weight of the pharmaceutical composition is outside the acceptable range, the pharmaceutical composition The intended target weight of the pharmaceutical composition is always within the acceptable range of variation.
  • the process of the invention comprises one or more further steps selected from the group consisting of spheronizing the resulting pharmaceutical composition, comminuting the resulting pharmaceutical composition, coating the resulting pharmaceutical composition, and combinations thereof.
  • the pharmaceutical composition obtained after extrusion and cutting can be further processed prior to administration to a patient, for example, by application of coatings or strain.
  • the pharmaceutical composition may be, for example, a precursor of a tablet or a pellet. If the pharmaceutical composition is a precursor of a tablet or a pellet, in the process according to the invention after extrusion and cutting, spheronization of the cut extrudate pieces is generally carried out.
  • An implant can also be subjected to a change in shape after extrusion and cutting.
  • a mixture e.g. a powder mixture of one or more active ingredients in combination with one or more preferably biodegradable polymers and optionally other pharmaceutically acceptable excipients.
  • Preferred active ingredients, especially for implants are psychotropic drugs, preferably antischizophrenics, e.g. Risperidone, or peptides or proteins. More preferably, an implant comprises an active agent selected from the group of hormones or hormone antagonists and agonists, e.g. LHRH or LHRH antagonists, such as anastrozole. Also preferred are goserelin, leuprorelin and octreotide. Also proteohormones such as e.g. Somatropin or interferon, a tissue hormone with antiviral and antitumor effects and its derivatives, can be used.
  • an active agent selected from the group of hormones or hormone antagonists and agonists, e.g. LHRH or LHRH antagonists, such as anastrozole.
  • goserelin, leuprorelin and octreotide are also preferred.
  • proteohormones such as e.g. Somatropin or interferon, a tissue hormone with
  • the pharmaceutical composition according to the invention contains as active ingredient the peptide oxytocin or a pharmaceutically acceptable salt or derivative thereof and is used inter alia for use in a method for the treatment of neuropsychiatric disorders, in particular depression, bipolar disorder, schizophrenia, childhood schizophrenia or autism.
  • Compositions according to the invention provided a sufficiently rapid release of active ingredient, can alternatively also be used, for example, in a method for Initiation or improvement of labor pains as oxytocin causes contraction of the uterine muscle.
  • the active substance used is a pharmaceutically acceptable salt of oxytocin, this is especially selected from oxytocin acetate, oxytocin phosphate or oxytocin pamoate.
  • a derivative of oxytocin is meant a compound having a similar chemical structure, optionally in the form of a salt, which as a result exhibits a similar or substantially equal therapeutic effect, in particular with regard to its use in a method for the treatment of a neuropsychiatric disorder.
  • This may in particular be a natural or synthetic, therapeutically active peptide analogue or chemically modified derivative of oxytocin or a salt thereof.
  • Oxytocin derivatives further include chemically modified peptide analogs of oxytocin or a salt thereof.
  • Peptide analogs of oxytocin are peptides that are formally derived from the natural, human oxytocin by an exchange, addition and / or omission of one or more amino acid building blocks.
  • the amino acid sequence of the peptide analogues is at least 80%, in particular at least 90% identical to the amino acid sequence of natural, human oxytocin.
  • chemical modification of oxytocin or a peptide analog thereof may involve amidation at the carboxyl terminus, use of D-amino acids in the peptide sequence, incorporation of small non-peptidic moieties, and / or modification of the amino acid moieties themselves, e.g. by alkylation or esterification of their side chains exist.
  • a derivative of oxytocin having a similar or substantially the same effect may also be a precursor or a metabolite of oxytocin or another derivative of oxytocin.
  • the derivative of oxytocin is a compound as in claim 2 and in paragraphs 14 to 16 of European patent EP 1 370 277 B1 disclosed.
  • the derivative is selected from the group of compounds as disclosed in claim 3 and in paragraph 17 of European patent EP 1 370 277 1.
  • the compounds mentioned are incorporated by reference in the disclosure of the present patent application.
  • the derivative of oxytocin may be one of the compounds as shown on page 7, line 5 through line 15, especially line 7 through line 15 of PCT application WO 201/145051 A1.
  • the compounds mentioned are likewise incorporated by reference into the disclosure of the present patent application.
  • the active ingredient is preferably entrapped or bound in a matrix.
  • the matrix preferably consists entirely of physiologically compatible materials which, after release of the active substance from the implant, either remain in the body or can be removed from the body or degrade or be absorbed during or after the release of the active substance in the body.
  • Preferred examples of matrix materials are polymers, copolymers and lipids.
  • the pharmaceutical composition of the present invention is preferably an implant.
  • Implants are implantable drug depots that release an active ingredient over a longer period of time and can therefore be used for the long-term treatment of diseases.
  • the release of the active ingredient e.g., oxytocin or a pharmaceutically acceptable salt or derivative thereof
  • release over a period of at least one month means release over a period of at least four weeks, i. of at least 28 days.
  • a release over a period of at least three months means release over a period of at least twelve weeks, i. of at least 84 days.
  • the sustained release of the drug from the implant is preferably achieved by the implant containing one or more preferably biodegradable polymers, such as polyester.
  • biodegradable polymers that due to the natural water balance in the human body by Hydrolysis are degraded after the implant has been injected into a patient, preferably subcutaneously.
  • the active substance enclosed or bound in the polymer matrix is released in a controlled manner in vivo and released to the patient over a longer period of time (depot function).
  • Preferred examples of hydrolysis-biodegradable polymers are homopolymers and copolymers of lactic acid and / or glycolic acid, especially polylactides and poly-lactide-co-glycolides.
  • implants according to the invention may comprise a polymer / active substance combination of poly-lactide-co-glycoid and active substance (eg oxytocin or a pharmaceutically acceptable salt or derivative thereof).
  • active substance eg oxytocin or a pharmaceutically acceptable salt or derivative thereof.
  • the implant contains one or more other pharmaceutically acceptable excipients.
  • Other preferred implants include a polymer-drug combination of poly-lactide-co-glycolide and goserelin.
  • the implants according to the invention containing oxytocin or a pharmaceutically acceptable salt or derivative thereof are preferably used for the treatment of neuropsychiatric disorders, in particular depression, bipolar disorder, schizophrenia, childhood schizophrenia or autism.
  • An implant can be of any conventional shape. Suitable forms of the implant are cylindrical or the like. Preferably, an implant in the form of a cylindrical rod made of the polymer / drug matrix is formed. Such an implant can be manufactured by extrusion. Alternatively, an implant may be spherical, e.g. in the form of a pellet, or the like.
  • an implant in particular a cylindrical rod, are a length of 5 to 25 mm, more preferably of 10 to 20 mm, and a cross section of 0.8 to 2.5 mm, more preferably 1, 1 to 1, 6 mm ,
  • an implant comprises from 0 to 50% by weight, more preferably from 5 to 40% by weight, and most preferably from 15 to 30% by weight, active ingredient and from 50 to 100% by weight, more preferably from 60 to 95% by weight, and more preferably from 70 to 85% by weight, of biodegradable polymer.
  • the total mass of the implant is from 10 to 100 mg, more preferably from 15 to 75 mg, and most preferably from 20 to 50 mg.
  • an implant according to the invention is intended for the treatment of neuropsychiatric disorders, it is preferably composed such that it releases the active ingredient, ie oxytocin or a pharmaceutically acceptable salt or derivative thereof, preferably by subcutaneous injection at a dose of 80 to 160 pg per day.
  • a 1-month implant ie, an implant that releases the drug for 4 weeks, preferably contains 2.25 mg to 4.5 mg of drug for the treatment of neuropsychiatric disorders, while a 3-month implant.
  • an implant that releases the drug for 12 weeks preferably contains 6.7 mg to 13.4 mg of active ingredient for the treatment of neuropsychiatric disorders.
  • the amount of drug to be contained in an implant may vary beyond the dimensions of the implant, i. its length and / or its cross-section, and / or the active ingredient content of the implant can be adjusted.
  • the amount of active ingredient of the implant in the amount of 2.25 mg to 4.5 mg preferably results from an active substance content of the implant of 20 to 30% by weight and a length or a cross section of the implant from 10 to 18 mm or 1, 10 to 1, 25 mm.
  • the amount of active ingredient of the implant in the amount of 6.7 mg to 13.4 mg preferably results from an active ingredient content of the implant of 25 to 35% by weight and a length or a cross section of the implant of 15 to 25 mm or 1, 50 to 1, 70 mm.
  • a pharmaceutical composition such as an implant, described above, a mixture comprising (i) an active agent, e.g. Oxytocin or a pharmaceutically acceptable salt or derivative thereof, and (ii) containing at least one pharmaceutically acceptable excipient, extruded by means of an extrusion device, and subsequently cutting the resulting extrudate.
  • an active agent e.g. Oxytocin or a pharmaceutically acceptable salt or derivative thereof
  • Extrusion is the application of pressure to a mass until it flows through one or more openings of defined size (press channels).
  • the extrusion according to the invention may in particular be a moisture extrusion or a melt extrusion.
  • a liquid medium at room temperature usually water
  • the liquid fraction is usually removed in a later drying step.
  • melt extrusion if the liquid fraction consists of a meltable substance, it is extruded at a temperature above the melting point; the solidification is achieved by subsequent cooling, wherein the liquid portion solidifies, according to the invention, a melt extrusion is preferred.
  • homogenization of the mixture to be extruded is carried out before the extrusion.
  • the mixture to be extruded is a powder mixture
  • different methods of powder homogenization can be used according to the invention. These include in particular:
  • An active ingredient is incorporated into a polymer melt, homogeneously suspended or dispersed therein.
  • the resulting mixture of polymer and active ingredient is then added to a pharmaceutical composition, e.g. an implant, further processed, e.g. by extruding or pressing.
  • a polymer is dissolved in a suitable organic solvent (e.g., dichloromethane) and then mixed with an aqueous or organic solution (e.g., methanolic) of the active ingredient.
  • a suitable organic solvent e.g., dichloromethane
  • an aqueous or organic solution e.g., methanolic
  • Hydrophilic active ingredients optionally in aqueous solution, are thereby suspended in the organic polymer solution, dispersed or emulsified, for example as w / o emulsion.
  • the solvents are e.g. removed at elevated temperature ("evaporated").
  • the resulting homogenized mixture of polymer and drug is then added to a pharmaceutical composition, e.g. an implant, a pellet or a tablet, further processed.
  • Polymer and active ingredient are combined together in a suitable solvent, e.g. Acetic acid dissolved.
  • a suitable solvent e.g. Acetic acid dissolved.
  • the solution is deep-frozen at -40 to -35 ° C and then lyophilized at a pressure of 0.08 mbar, i. freeze-dried. Primary drying takes place at 15 to 20 ° C, secondary drying at 30 ° C.
  • a homogeneous, fine powder is obtained, which can then be processed directly mitteis extrusion.
  • EP 1 392 248 describes a process for the solvent-free homogenization of polymer and active substance by cold milling with the aid of a cryomill.
  • polymer and active substance are jointly cooled down as raw materials to a temperature used in cryotechnology and homogenized together below the glass transition temperature of the polymer, wherein the steps of cooling down and homogenizing can be carried out several times in succession.
  • cryogenic method is used.
  • the extrusion is generally carried out as a piston or screw extrusion, preferably piston extrusion, usually at 55-120 ° C., preferably 65-95 ° C., particularly preferably 75-85 ° C.
  • the cutting unit is part of the extrusion device.
  • the cutting unit is not part of the extrusion apparatus but an apparatus associated therewith.
  • the extrudate is transported from the extruder by means of a conveyor belt or conveyor trough to the balance after being pressed out.
  • a conveyor belt from the company. MTF technology, Bergneustadt, Germany can be used.
  • the pharmaceutical composition produced by the cutting process is weighed.
  • the weighing preferably takes place immediately after cutting, e.g. at most 30 seconds, preferably at most 20 seconds, more preferably at most 10 seconds after the cutting operation, most preferably at most 5 seconds after the cutting operation of the respective pharmaceutical composition.
  • any suitable weighing device can be used.
  • analytical balances with a readability of 0.01 mg, e.g. Mettler-Toledo type
  • the weight of the pharmaceutical composition (eg, the implant weight) determined by the balance is communicated to a control device (eg, a computer). Transmission can be via a cable or wireless.
  • a control device eg, a computer on which suitable software is executed and preferably stored, it is determined whether the measured weight is within the predetermined weight range. This predetermined weight range is usually entered before the start of extrusion in the control device or the computer. If the measured weight is outside the predetermined weight range, the control device or the computer transmits a control signal to the extruder or an apparatus associated with it, which changes a parameter of the extrusion apparatus such that subsequently produced pharmaceutical compositions have a weight which is within the predetermined range.
  • the transmission of the control signal to the extruder or a device associated therewith may be via a cable or wireless.
  • the control device or the computer may be a control device or computer separate from the extrusion device (see FIGS. 3A, 3B, 3F), but may also be incorporated into the extrusion device (see FIG. 3E) into which Cutting unit (see Figure 3D) and / or in the weighing device (see Figure 3C) to be integrated.
  • the weighing device may be a separate balance (eg, FIGS. 3A, 3B, 3D, 3E), but it may also be integrated into the extrusion device (eg, FIG. 3F).
  • the extrusion device comprises the control device or the computer and the weighing device.
  • the control signal need not be transmitted directly to the extruder, it may also be transferred to a device associated with the extruder.
  • Devices associated with the extruder are, for example, the cutting unit or other control devices that can control the extruder device.
  • FIG. 1 Various embodiments of the transmission of the control signal are shown schematically in FIG. 1
  • FIG. 1 A preferred embodiment of the entire process according to the invention is shown schematically in FIG.
  • the weight control takes place in such a way that the mean weight of a plurality of successively produced pharmaceutical compositions is determined and used as a controlled variable.
  • the mean weight GMW may be determined, for example, by N pharmaceutical compositions, wherein N is preferably 2 to 20, more preferably 3 to 15, most preferably 4 to 10. If the determined average weight is outside the predetermined weight range, the control device or the computer transmits a control signal to the extruder or an associated device which changes a parameter of the extrusion device such that the average weight of the subsequently produced pharmaceutical compositions is within the predetermined range ,
  • the control signal transmitted to the extrusion device alters a parameter of the extrusion device which affects the weight of the pharmaceutical composition, such that subsequently produced pharmaceutical Compositions have a weight which is within the predetermined range.
  • the parameter can be one of the following parameters:
  • the cutting process is preferably adjusted as follows: in the case of check weighing of a pharmaceutical composition obtained after extrusion and cutting (eg an implant) whose weight is outside the predetermined range, the software provides feedback to the extruder, the control device and / or the cutting unit, after which Cutting unit the time between two cuts modified so that the subsequently produced pharmaceutical compositions (eg implants) again have a weight within the predetermined range.
  • the software provides feedback to the extruder, the control device and / or the cutting unit, after which Cutting unit the time between two cuts modified so that the subsequently produced pharmaceutical compositions (eg implants) again have a weight within the predetermined range.
  • Typical time intervals between two cuts are about 5-15 seconds in the case of implants (depending on the extrusion rate and on the product).
  • the adjustment of a desired weight of the pharmaceutical compositions (eg implants) over the variation of the time intervals between two sections has the advantage that the required time intervals are produced very quickly, typically within a few seconds after the detection of the software, outside the desired range, can be adjusted and also on the change in the length of the pharmaceutical composition, such as the implant, even the smallest mass changes are possible.
  • a length variance of approx. ⁇ 0.2 - 0.3 mm which again depends on the absolute lengths of the pharmaceutical composition. This variance is also available when cutting by hand and is therefore acceptable. If the measured weight is too high, the time between two consecutive cuts is shortened. If the measured weight is too low, the time between two successive cuts is increased.
  • a pharmaceutical composition eg an implant
  • the punch path is shortened between two successive cuts. If the measured weight is too low, the Stempeiweg is increased between two consecutive cuts.
  • Another possibility is to control the force with which the extrusion piston forces the extrudate through the extrusion die (s).
  • a pharmaceutical composition eg an implant
  • the software provides feedback to the extruder and / or the control device, whereupon the extruder gives the force with which the extrusion piston extrudes through the extrusion die (s), modified so that the subsequently produced pharmaceutical compositions (eg implants) again have a weight within the predetermined range.
  • the extrusion process is adjusted as follows: if, during control weighing of a manufactured pharmaceutical composition (eg, an implant), its weight is outside the predetermined range, the software provides feedback to the extruder and / or the controller, whereupon the extruder will adjust the extrusion rate modifies that the subsequently produced pharmaceutical compositions (eg implants) again have a weight within the predetermined range.
  • a manufactured pharmaceutical composition eg, an implant
  • Typical extrusion speeds are 0.002 - 0.15 mm / s (piston extruder) or 10 - 70 rpm (screw extruder).
  • the extrusion speed is reduced. If the measured weight is too low, the extrusion speed is increased.
  • the adjustment of the desired weights of the pharmaceutical compositions e.g. the implant weights, even via a variation of the diameter of the extruder die, although even small changes in diameter lead to relatively large changes in mass.
  • the diameter of the extruder die is reduced. If the measured weight is too low, the diameter of the extruder die is increased.
  • the extrusion temperature may be varied, thereby changing the viscosity of the extrudate, and thus also the diameter of the extrudate exiting the extruder.
  • the change in the temperature of the extrudate is quite slow, so that the adjustment to a desired weight of the pharmaceutical composition, e.g. to a desired implant weight, in this case should take a few minutes.
  • the predetermined range of the weight outside which the automatic readjustment starts is freely selectable. It can thus be specified from when it should come to a readjustment. If one chooses the range too narrow (eg target weight +/- 0.5%), there is often readjustment, which can be disadvantageous for the process. If you choose it very far (eg target weight + -5%), then it may be that individual masses of the pharmaceutical compositions, such as implant masses, outside the desired tolerance range of, for example, +/- 5%, because there are always slight fluctuations and especially because the readjustment in some embodiments does not affect the immediate subsequent pharmaceutical composition, but only later.
  • the "predetermined range” outside which readjustment is preferably narrower than the actually acceptable range of variation of the weight of the pharmaceutical composition, which is referred to herein as the "acceptable range of weight” or “acceptable range.”
  • the acceptable range of variation will be When the weight of the pharmaceutical composition is outside the acceptable range of fluctuation, the particular pharmaceutical composition must usually be sorted out and discarded
  • the method includes the step of removing or sorting out the pharmaceutical composition pharmaceutical composition, if it has a weight outside the acceptable range of variation.
  • the predetermined range is equal to the acceptable range of fluctuation, the following problem may arise: It is possible that the readjustment does not directly affect the weight of the next pharmaceutical composition, but takes effect only with a delay. For example, if a first implant outside the predetermined range, and then follows a readjustment, it may be that the weight of the second implant produced immediately thereafter still lies outside the predetermined range, and only the third or even only the fourth implant again within For this reason, it is advantageous if the predetermined range is narrower than the acceptable range of variation. In the above example, the second and possibly the third implant would be outside the predetermined range but still within the acceptable range of variation.
  • the acceptable variation range aS is equal to the target weight Z +/- Y%
  • the predetermined range vB Z +/- n * Y%, where Y is 0.5 to 10, and 0 ⁇ n ⁇ 1 ,
  • the rate of rejects in the process of the present invention is preferably at most 10%, more preferably at most 5%, more preferably at most 4%, even more preferably at most 3%, even more preferably at most 2%, most preferably at most 1%.
  • Typical rates of rejects in the process according to the invention are ⁇ 1% (see examples). It should be noted that the rate of rejects depends on the acceptable range of variation. If this is narrow, the rate of rejects is higher than in cases where the acceptable range of variation is wider.
  • the relative standard deviation, also called the coefficient of variation, of the individual masses of those pharmaceutical compositions, e.g. Implants made according to the conventional method (including or excluding the scrap compositions such as reject implants) are typically about> 3% to 7%, more preferably 4 to 6%.
  • the relative standard deviation of the individual masses of those compositions are usually 0.1-3%, typically 0.5-2%.
  • the relative standard deviation VarK is the quotient of the standard deviation ⁇ (based on a random sample) of the implant weight X and the mean value of the implant weight X, X.
  • the standard deviation based on a sample is calculated as follows:
  • n is the sample size
  • the readjustment can be carried out in such a way that the parameter to be changed is first changed by a specific control value, irrespective of how high the deviation of the measured weight from the target weight is. If it turns out that the subsequently produced pharmaceutical compositions are still outside the prescribed range, then an increase in the control value takes place.
  • the control value is calculated on the basis of the determined weight of the pharmaceutical composition. The higher the deviation of the weight from the given range, the higher the control value. This variant has the advantage that the control value is adjusted automatically and no manual intervention must be made.
  • the amount of the percentage change of the parameter may be equal to the amount of the percentage variation of the predetermined range around the target target weight. For example, if the predetermined range is the target weight Z +/- 2%, then the amount of change of the parameter may be 2%. It may also be lower in another embodiment, e.g. 1% or 1, 5% for a given range of Z +/- 2%.
  • a separation or removal of pharmaceutical compositions having a weight which is outside the predetermined range takes place.
  • a separation or removal of pharmaceutical compositions having a weight that is outside the acceptable range of fluctuation occurs.
  • the step of separating or removing is preferably carried out automatically.
  • the weighing device may transmit a signal to a severing device if the weight is outside the predetermined range or outside the acceptable range of fluctuation.
  • the severing device then removes the pharmaceutical composition whose weight is outside the predetermined one due to the signal Range or outside the acceptable range.
  • extrusion device for carrying out the method according to the invention.
  • the extrusion device comprises at least the following elements:
  • a weighing device for determining the weight of the cut extrudate.
  • the weighing device is coupled to a control device which can change at least one parameter of the extruder, which has an effect on the weight of the pharmaceutical composition to be produced, as a function of the measured weight.
  • the parameter which affects the weight of the pharmaceutical compositions to be produced is preferably selected from the group consisting of the time between two consecutive cuts of the extrudate, the distance traveled by the piston of a piston extruder between two successive cutting operations, the force, with the piston of a piston extruder presses the extrudate through the extrusion die (s), the diameter of the extrusion die, the extrusion temperature, the extrusion speed, and combinations thereof.
  • the control device is preferably a computer, for example a computer or another suitable computer unit.
  • the coupling of the weighing device to a control device can be realized by cable or "wirelessly.” The same applies to the coupling of the control device to the extruder for the transmission of the control signal
  • the control device or the computer can be separated from the extrusion device (s). It can also be integrated into the extrusion device (see FIG. 3E), into the cutting unit (see FIG. 3D) and / or into the weighing device (see FIG. 3C)
  • the weighing device may be a separate balance (eg, FIGS. 3A, 3B, 3D, 3E), but it may also be integrated into the extrusion device (eg, FIG In particular embodiment, the extrusion device comprises the control device or the computer and the weighing device,
  • the controller need not be directly coupled to the extruder, it may also be coupled to a device associated with the extruder.
  • Devices associated with the extruder are, for example, the cutting unit or other control devices that can control the extruder device.
  • the extrusion device may comprise a screw extruder (single or twin screw extruder), a piston extruder or another type of extruder.
  • a screw extruder single or twin screw extruder
  • a piston extruder or another type of extruder.
  • the material to be extruded is not conveyed by a screw, but pressed by one or two impeller (also referred to as rotor) from the inside through a horizontal annular die.
  • extruders Conventional embodiments of extruders are described, for example, in the book “Polymer Extrusion” (2014, 5, edition, ISBN 978-1-56990-516-6) by Chris Rau endaal. These extruders can also be used in the process according to the invention and form part of the disclosure of this patent application,
  • a further aspect of the present invention is the use of a control device which can change at least one parameter of an extruder, which has an effect on the weight of the extrudate, for carrying out a method according to the invention.
  • the invention further relates to the use of a control device that can change at least one parameter of an extruder, which has an effect on the weight of the extrudate, for producing an extrusion device which is suitable for carrying out a inventive method is suitable.
  • the invention relates to the use of a control device which can change at least one parameter of an extruder, which has an effect on the weight of the extrudate, for producing an extrusion device according to the invention.
  • weight in this application is synonymous with the term “mass used” unless otherwise stated.
  • the present invention relates to the following embodiments [1] to [29], but is not limited thereto:
  • a process for the preparation of a pharmaceutical composition in which a mixture containing at least one active ingredient and at least one pharmaceutically acceptable excipient is extruded by means of an extrusion apparatus and the resulting extrudate is cut to form the pharmaceutical composition, characterized in that the pharmaceutical composition is weighed, and in the event that the weight of the pharmaceutical composition is outside a predetermined range, at least one parameter of the extrusion device that affects the weight of the pharmaceutical compositions to be produced is changed such that subsequently produced pharmaceutical compositions have a weight that is within the predetermined range.
  • the parameter of the extrusion device which affects the weight of the pharmaceutical compositions to be produced, is selected from the group consisting of the time between two consecutive cuts of the extrudate , the distance traveled by the piston of a piston extruder between two consecutive cutting operations, the force with which the piston of a piston extruder drives the piston Extrude through the extrusion die (s), the diameter of the extruder die, the extrusion temperature, the extrusion rate, and combinations thereof.
  • the adjuvant is a polymer, in particular a homopolymer, a copolymer or a mixture thereof, containing glycolide and / or lactide portions.
  • a collective of pharmaceutical compositions having a weight distribution with a relative standard deviation of 0.1-3%, typically 0.5-2%.
  • compositions wherein the compositions preferably have such a weight distribution that more than 90%, preferably more than 95%, in particular more than 99% of the
  • Compositions have a weight that deviates from the target weight of at most 5% by weight.
  • composition is an implant.
  • [1 1] A collective of pharmaceutical compositions, wherein the pharmaceutical compositions can be prepared by a method according to any one of embodiments 1 to 7.
  • An extrusion apparatus for performing a method according to any one of Embodiments [1] to [7], comprising an extruder having an extrusion die for Generating at least one extrudate strand, a cutting device and the
  • Extruder downstream conveyor characterized in that the extrusion device further comprises a weighing device for determining the weight of the cut extrudate, wherein the weighing device is coupled to a control device, and the control device at least one parameter of the extruder, based on the weight of the pharmaceutical compositions to be produced can change depending on the measured weight,
  • the extrusion apparatus according to the embodiment [12], characterized in that the parameter having an effect on the weight of the pharmaceutical compositions to be produced is selected from the group consisting of the time between two consecutive cuts of the extrudate, the course which the Piston of a piston extruder between two consecutive cutting operations, the force with which the piston of a piston extruder forces the extrudate through the extrusion die (s), the diameter of the extruder die, the extrusion temperature, the extrusion rate, and combinations thereof.
  • a process for producing a pharmaceutical composition in which a mixture containing (i) oxytocin or a pharmaceutically acceptable salt or derivative thereof and (ii) at least one pharmaceutically acceptable excipient is extruded by means of an extrusion apparatus and the resultant extrudate is cut is to give the pharmaceutical composition, characterized in that the pharmaceutical composition is weighed, and in the case that the weight of the pharmaceutical composition is outside a predetermined range, at least one parameter of the extrusion device, which is based on the weight of the pharmaceutical Effecting compositions, is changed in such a way that subsequently produced pharmaceutical compositions have a weight which is within the predetermined range.
  • the adjuvant is a biodegradable polymer
  • the biodegradable polymer is more particularly a homopolymer, a copolymer or mixtures thereof containing glycolide and / or lactide moieties.
  • a collective of pharmaceutical compositions containing oxytocin or a pharmaceutically acceptable salt or derivative thereof which has a weight distribution with a relative standard deviation of 0-1-3%, typically 0.5-2%.
  • a collective of pharmaceutical compositions containing oxytocin or a pharmaceutically acceptable salt or derivative thereof, wherein the pharmaceutical compositions can be prepared by a process according to any of embodiments [16] to [22].
  • An implant containing oxytocin or a pharmaceutically acceptable salt or derivative thereof as an active ingredient and at least one pharmaceutically acceptable excipient the implant containing the active ingredient after the, preferably subcutaneous, injection over a period of at least 1 week, preferably at least 1 month For example, at least three months, releases.
  • a neuropsychiatric disorder such as depression, bipolar disorder, schizophrenia, childhood schizophrenia or autism.
  • the mixture is placed in an extrusion cylinder (part of the rheograph, length 230 mm, diameter 20 mm) and heated in the apparatus Rheograph 25E within 25 minutes at 81 ° C.
  • the extrusion is started by a 1.45 mm die with a constant force of 5000 N (giving a speed of extrudate exit in the range of 0.08 - 0.1 1 mm / s).
  • the cutting unit on the rheograph both jaws are flexible and move together when cutting, optionally one jaw can be fixed and the second jaw is flexible and runs against the first jaw when cutting) is adjusted to cut strings of 10 cm length.
  • the strands are then manually cut into implants with a nominal length of 14.5 mm (by hand with a ceramic or metal blade.)
  • the complete device was specially developed for us by a meta maker.
  • the actual length is mitteis Mitutoyo a calipers, type AOS Digimatic measured).
  • the target weight of the implants is 20.34 mg.
  • the control weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.97 mg (sample with rejects, i.e. including reject implants)
  • a mixture of 5.00 g of oxytocin acetate and 18.00 g of Resomer® RG 503 H (Prepared from: a poly (D, L-lactide-co-glycolide) having from 48 to 52 mole percent lactic acid units and from 52 to 48 mole percent glycolic acid units, an inherent viscosity of 0.32 - 0.44 dl / g (0.1% (w / v) in chloroform, 25 "C, Ubbelohde, size 0c glass capillary viscometer) and a M w of 24,000-38,000 g / mol are placed in a tumbler (type Turbula T2B) for The mixture is mixed in an extrusion cylinder (belonging to the rheograph, length 230 mm, diameter 20 mm) for 15 min at 23 rpm and heated in the apparatus Rheograph 25E within 25 minutes at 78 ° C.
  • a tumbler type Turbula T2B
  • the extrusion was started by a 1.20 mm die at a constant force of 8000 N (giving a speed of the extrudate exit in the range of 0.09 - 0.13 mm / s)
  • the cutting unit on the rheograph both jaws are flexible and move together when cutting
  • one jaw can be fixed and the second jaw is flexible and moves against the first jaw when cutting.) is adjusted so that strands of 10 cm in length are cut.
  • the strands are then manually cut into implants with a nominal length of 14.8 mm (by hand with a ceramic or metal blade.)
  • the complete device was specially developed for us by a metalworker.
  • the actual length is determined using a vernier caliper from Mitutoyo, type AOS Digimatic measured).
  • the target weight of the implants is 20.50 mg.
  • the control weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 1.03 mg (sample with rejects, i.e. including reject implants)
  • Standard deviation of individual weights 0.92 mg (sample without rejects, i.e. excluding reject reject implants)
  • a tumbler type Turbula T2B
  • the mixture is filled in an extrusion cylinder and heated to 81 ° C. in the apparatus Rheograph 25E within 25 minutes. After a further 45 minutes, the extrusion is started by a 1.45 mm die by means of a force of 5000 N (which results in a speed of the extrudate exit in the range of 0.08-0.11 mm / s).
  • the cutting unit on the rheograph is initially set to cut strands of 14.5 mm in length. The strands run directly after production via the checkweigher. There, a target weight of 20.34 mg is entered and with a deviation of ⁇ 2% from this weight, the automatic readjustment of the cutting unit starts by controlling the time between two cuts. If the deviation from the target weight in this case is X%, then the time is readjusted by -X%. In the contra-weighing, implants with a deviation of> ⁇ 5% from the sol weight are sorted out.
  • the extrusion is carried out at a constant speed of 0.02 mm / s (that is the speed with which the punch moves downwards) through a 1.15 mm nozzle
  • the cutting unit on the rheograph is initially set to cut strands of 16.5 mm in length.
  • the strands run directly after production via the checkweigher.
  • a target weight of 15.75 mg is entered and with a deviation of ⁇ 2% from this weight, the automatic readjustment of the extruder begins, with the force with which the punch presses the extrudate through the nozzle being controlled.
  • implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • a mixture of 2.50 g of Trptorelin pamoate and 18.70 g of Resomer® R 203S (manufacturer's instructions: a poly (L-lactide) having an M w of 18,000-28,000 and an inherent viscosity of 0.25-0.35 dl / g, 0.1% (w / w) / v) in chloroform, 25 ° C, Ubbelohde, size 0c glass capillary viscometer) are mixed in a free-fall mixer (type Turbula T2B) for 15 min at 23 rpm. The mixture is filled in an extrusion cylinder and heated to 82 ° C. in the apparatus Rheograph 25E within 25 minutes.
  • extrusion is started at a constant rate of 0.008 mm / s through a 1.75 mm die.
  • the cutting unit on the rheograph is initially set to cut strands of 17.5 mm in length.
  • the strands run directly after production via the checkweigher.
  • There a target weight of 32.35 mg is entered and with a deviation of ⁇ 2% of this weight, the automatic readjustment of the extruder begins, whereby the distance covered by the punch between two cuts is regulated.
  • a blend of 5.00 g of oxytocin acetate and 18.00 g of Resomer® RG 503 H (manufacturer's information: a poly (D, L-lactide-co-glycolide) having from 48 to 52 mole percent lactic acid units and from 52 to 48 mole percent glycolic acid units, an inherent viscosity of 0.32-0.44 dl / g (0.1% (w / v) in chloroform, 25 ° C, Ubbelohde, size 0c glass capillary viscometer) and a M w of 24,000-38,000 g / mol are suspended in a tumbler (Turbula T2B type) for 15 min mixed at 23 rpm.
  • a tumbler Teurbula T2B type
  • the mixture is filled in an extrusion cylinder and heated in the apparatus Rheograph 25E within 25 minutes at 78 ° C. After another 45 minutes, the extrusion is begun by a 1.20 mm die by means of a force of 8000 N (giving a punch speed in the range of 0.09 - 0.13 mm / s).
  • the cutting unit on the rheograph is initially set to cut strands of 14.8 mm in length. The strands run directly after production via the checkweigher. There, a target weight of 20.50 mg is entered and with a deviation of ⁇ 2% from this weight, the automatic readjustment of the cutting unit begins by controlling the time between two cuts.
  • the time is readjusted by -X%.
  • the control weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.31 mg (sample with rejects, i.e. including reject implants)
  • Standard deviation of individual weights 0.29 mg (sample without rejects, i.e. excluding reject reject implants)
  • the relative standard deviation of individual weights including reject implants has decreased from 5.0% to 1.5%, corresponding to a decrease of 70%.
  • the relative standard deviation of individual weights excluding reject implants has decreased from 4.5% to 1.4%, corresponding to a decrease of 69%.
  • the mixture is filled in an extrusion cylinder and heated in the apparatus Rheograph 25E within 30 minutes at 85 ° C. After a further 30 minutes, the extrusion is started at a constant speed of 0.016 mm / s (that is the speed with which the punch moves downwards) through a 1.15 mm nozzle.
  • the cutting unit on the rheograph is initially set to cut strands of 17.5 mm in length. The strands run directly after production via the checkweigher. There, a target weight of 15.20 mg is entered, and with a deviation of ⁇ 2% of that weight, the automatic readjustment of the extruder begins, with the force with which the punch presses the extrudate through the nozzle being controlled.
  • the controi weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.19 mg (sample with rejects, i.e. including reject implants)
  • Standard deviation of individual weights 0.18 mg (sample without rejects, i.e. excluding reject reject implants)
  • a mixture of 5.50 g of oxytocin pamoate and 17.70 g of Resomer® R 203 S (manufacturer's information: a poly (L-lactide) with an inherent viscosity of 0.25-0.35 di / g (0.1% (w / v) in chloroform, 25 ° C. Ubbelohde, size 0c giass capillary viscometer) and a Mw of 18,000 - 28,000 g / mol) are mixed in a free-fall mixer (Turbuia T2B type) for 15 min at 23 rpm. The mixture is filled in an extrusion cylinder and in the Device Rheograph 25E heated to 82 ° C within 25 minutes.
  • extrusion is started at a constant rate of 0.008 mm / s through a 1.75 mm die.
  • the cutting unit on the rheograph is initially set to cut strands 22.15 mm in length.
  • the strands run directly after production via the checkweigher.
  • a target weight of 41.85 mg is entered and with a deviation of ⁇ 2% of this weight, the automatic readjustment of the extruder begins, whereby the distance covered by the punch between two cuts is regulated.
  • the check weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.28 mg (sample with rejects, i.e. including reject implants)
  • Standard deviation of individual weights 0.27 mg (sample without rejects, i.e. excluding reject reject implants)
  • a mixture of 6.75 g oxytocin, 14.00 g Resomer® RG 503 H (manufacturer's instructions: a poly (D, L-lactide-co-glycolide) with 48 to 52 mole percent lactic acid units and 52 to 48 mole percent glycolic acid units, an inherent viscosity of 0.32-0.44 dl / g (0.1% (w / v) in chloroform, 25 ° C, Ubbelohde, size 0c glass capillary viscometer) and an M w of 24,000-38,000 g / mol) and 4.25 g Resomer® R 203 S (manufacturer's instructions: a Poly (L-lactide) having an inherent viscosity of 0.25-0.35 dl / g (0.1% w / v in chloroform, 25 ° C, Ubbelohde, size 0c glass capillary viscometer) and a Mw of 18,000-28,000
  • the Mixture is filled in an Exirusionszyiinder and heated in the device Rheograph 25E within 25 minutes at 82 ° C. After another 25 minutes, extrusion is started at a constant rate of 0.015 mm / s through a 1.25 mm die.
  • the cutting unit on the rheograph is initially set to cut strands of 15.0 mm in length.
  • the strands run after the manufacturing directly on the checkweigher, there is a target weight of 25.10 mg entered and with a deviation of ⁇ 2% of this weight, the automatic readjustment of the extruder, whereby the distance covered by the punch between two cuts, regulated ,
  • the check weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.28 mg (sample with rejects, i.e. including reject implants)
  • Standard deviation of individual weights 0.25 mg (sample without rejects, i.e. excluding reject reject implants)
  • Chloroform, 30 ° C, Ubbelohde, size 0c glass capillary viscometer)) are ground in a cryomill under liquid nitrogen for 10 minutes.
  • the mixture is filled in an extrusion cylinder and heated in the apparatus Rheograph 25E within 25 minutes at 75 ° C. After another 15 minutes, the extrusion is carried out by means of a constant Speed of 0.015 mm / s started by a 1.45 mm nozzle.
  • the cutting unit on the rheograph is initially set to cut strands of 18.5 mm in length. The strands run directly after production via the checkweigher. There a target weight of 27.0 mg is entered and with a deviation of ⁇ 2% from this weight, the automatic readjustment of the extruder begins, whereby the distance covered by the punch between two cuts is regulated.
  • Contro-weighing (balance: Mettler Toledo type XPE 105) is carried out with a tolerance of target weight ⁇ 5%. This means that implants with a deviation of> ⁇ 5% from the target weight are sorted out.
  • Standard deviation of individual weights 0.22 mg (sample with rejects, i.e. including reject implants)

Abstract

L'invention concerne un procédé d'extrusion pour la fabrication d'une composition pharmaceutique ainsi qu'un dispositif pour la mise en œuvre dudit procédé.
PCT/EP2015/058947 2014-04-30 2015-04-24 Procédé et dispositif pour la fabrication d'une composition pharmaceutique WO2015165821A1 (fr)

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CN201580030280.3A CN106413689A (zh) 2014-04-30 2015-04-24 制备药物组合物的方法和装置

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156913A (en) * 1976-09-24 1979-05-29 The Goodyear Tire & Rubber Company Method and apparatus for controlling the thickness of extruded stock
EP0858323A1 (fr) * 1996-09-04 1998-08-19 DEGHENGHI, Romano Procede de fabrication d'implants contenant des peptides bioactifs
WO2002013793A2 (fr) * 2000-08-16 2002-02-21 Rexall Sundown, Inc. Procede de fabrication de comprimes et compositions de comprimes produites conformement audit procede
WO2004078147A2 (fr) * 2003-03-05 2004-09-16 Pr Pharmaceuticals Preparations a base d'oxytocine a liberation controlee et leurs procedes d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4156913A (en) * 1976-09-24 1979-05-29 The Goodyear Tire & Rubber Company Method and apparatus for controlling the thickness of extruded stock
EP0858323A1 (fr) * 1996-09-04 1998-08-19 DEGHENGHI, Romano Procede de fabrication d'implants contenant des peptides bioactifs
WO2002013793A2 (fr) * 2000-08-16 2002-02-21 Rexall Sundown, Inc. Procede de fabrication de comprimes et compositions de comprimes produites conformement audit procede
WO2004078147A2 (fr) * 2003-03-05 2004-09-16 Pr Pharmaceuticals Preparations a base d'oxytocine a liberation controlee et leurs procedes d'utilisation

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