GB2540400A - Method and production system for producing a pharmaceutical extrudate comprising a low-dose active pharmaceutical ingredient - Google Patents

Method and production system for producing a pharmaceutical extrudate comprising a low-dose active pharmaceutical ingredient Download PDF

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Publication number
GB2540400A
GB2540400A GB1512436.5A GB201512436A GB2540400A GB 2540400 A GB2540400 A GB 2540400A GB 201512436 A GB201512436 A GB 201512436A GB 2540400 A GB2540400 A GB 2540400A
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GB
United Kingdom
Prior art keywords
extrusion
screw extruder
extruder device
extrudate
section
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
GB1512436.5A
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GB201512436D0 (en
Inventor
Khinast Johannes
Koscher Gerold
Klein Thomas
Bresciani Massimo
Llusa Marcos
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Res Center Pharmaceutical Eng GmbH
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Res Center Pharmaceutical Eng GmbH
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Priority to GB1512436.5A priority Critical patent/GB2540400A/en
Publication of GB201512436D0 publication Critical patent/GB201512436D0/en
Publication of GB2540400A publication Critical patent/GB2540400A/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/08—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of suppositories or sticks
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate 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
    • A61K9/146—Intimate 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 macromolecular compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
    • B29C48/395—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders
    • B29C48/40—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/78—Thermal treatment of the extrusion moulding material or of preformed parts or layers, e.g. by heating or cooling
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/78—Thermal treatment of the extrusion moulding material or of preformed parts or layers, e.g. by heating or cooling
    • B29C48/80—Thermal treatment of the extrusion moulding material or of preformed parts or layers, e.g. by heating or cooling at the plasticising zone, e.g. by heating cylinders
    • B29C48/802—Heating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/88—Thermal treatment of the stream of extruded material, e.g. cooling
    • B29C48/91—Heating, e.g. for cross linking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/022—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the choice of material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
    • B29C48/395—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders
    • B29C48/40—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders
    • B29C48/405—Intermeshing co-rotating screws

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Mechanical Engineering (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Thermal Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A method for producing an pharmaceutical extrudate (101) comprising a low dose active pharmaceutical ingredient in which an extrusion material is conveyed by an extruder screw (102) of a screw extruder device (100) from a feeding section (103) of the screw extruder device (100) to an output section (108) of the screw extruder device (100). An extrusion liquid (109) is pumped with a predetermined volumetric flow rate, wherein the extrusion liquid (109) comprises a carrier solution in which a dosed quantity of the active pharmaceutical ingredient is suspended, dissolved or melted. The extrusion liquid (109) is added to the extrusion material within an injection section (106) of the screw extruder device (100). The extrusion liquid (109) is mixed with the extrusion material within a mixing section (107) of the screw extruder device (100) to produce the pharmaceutical extrudate (101). The pharmaceutical extrudate (101) is outputted at the output section (108) of the screw extruder device (100). The carrier solution may be polyethylene glycol and distilled water. The preferred active ingredient is ibuprofen. A production system for producing a pharmaceutical extrudate is also claimed.

Description

Method and production system for producing a pharmaceutical extrudate comprising a low-dose active pharmaceutical ingredient
Field of invention
The present invention relates to a method for producing pharmaceutical extrudate comprising a low content of an active pharmaceutical ingredient. Furthermore, the present invention relates to a production system for producing a pharmaceutical extrudate comprising an active pharmaceutical ingredient.
Art Background
Many prospective active pharmaceutical ingredients (called APIs) are highly active with doses in the micro- or low milligram-range, and thus, need to be added in small quantities to a formulation. In batch processing, the API is typically granulated and hereby mixing and content-uniformity problems are reduced. However, in continuous manufacturing creating a continuous low-dose powder stream is highly challenging, especially for cohesive powders and powder flow rates below for example lkg/h. This is due to the fact that many powders flow poorly and in chunks (even if chunks are small), especially for cohesive or needle-shaped API powders that tend to form agglomerates and clumps. In loss-in-weight (LIW) feeders this leads to a highly variable dosing flow and, although the control systems can ensure that the time-integrated flow rate is close to the desired one, medium-to-high frequency oscillations cannot be eliminated.
Thus, accurate powder feeding of low-dose APIs is challenging and a well-known hurdle for continuous manufacturing of potent formulations.
Furthermore, hot-melt extrusion is a process that can be used to produce formulations for APIs that have poor solubility and/or permeability. For example, APIs can be formulated as crystalline solid dispersions, as amorphous solid dispersions or as solid solutions. In addition, nano-particles can be embedded in a polymeric matrix.
Summary of the Invention
It may be an object of the present invention to produce a pharmaceutical comprising constantly distributed low dosed and highly active pharmaceutical ingredients.
This object is solved by a method for producing a pharmaceutical extrudate comprising an active pharmaceutical ingredient and by a production system for producing a pharmaceutical extrudate comprising an active pharmaceutical ingredient according to the independent claims.
According to a first aspect of the present invention, a method for producing a pharmaceutical extrudate comprising a low-dose active pharmaceutical ingredient is presented. An extrusion material (e.g. a powdery material) is conveyed by an extruder screw of a screw extruder device from a feeding section of the screw extruder device to an output section of the screw extruder device. An extrusion liquid is pumped with a predetermined volumetric flow rate, wherein the extrusion liquid comprises a carrier solution in which a dosed quantity of the active pharmaceutical ingredient is mixed. The extrusion liquid is for example a suspension of API particles, an API solution or a melted API. The extrusion liquid is added to the extrusion material (e.g. powdery material) within an injection section of the screw extruder device. The extrusion liquid is mixed with the extrusion material within a mixing section of the screw extruder device to produce the pharmaceutical extrudate. The pharmaceutical extrudate is outputted at the output section of the screw extruder device.
The screw extruder device may comprise a single screw for transporting the extrusion material from the feeding section to the output section of the extruder. However, the screw extruder may also be a double screw extruder comprising two transporting screws for transporting the extrusion material.
The screw extruder device further comprises a feeder unit which feeds the extrusion material into the feeding section of the screw extruder device. Next, the extruder screw transports the extrusion material along a transport direction to an injection section of the screw extruder device, where the extrusion liquid may be injected, for example by an injection device. Downstream along the transport direction of the injection section the screw extruder device comprises a mixing section. Along the mixing section the extrusion liquid is mixed with the extrusion material while being transported by the extruder screw.
By the approach of the present invention a constant and homogeneous mixing between the extrusion (such as powdery material) and extrusion liquid can be achieved, because of the steady injection of liquid phase of the extrusion liquid which is mixed to the extrusion material.
The screw extruder device may further comprise heating elements. For example, along the mixing section the extrusion material and extrusion liquid can be heated such that the extrusion liquid evaporates and the API remains within the extrusion material.
At the output section of the screw extruder device, the pharmaceutical extrudate(consisting of the extrusion material and the extrusion liquid or the extrusion material and the API (because the liquid part of the extrusion liquid is evaporated)) is outputted by pressing the extrudate through an extruder nozzle having a predefined cross-section. The pharmaceutical extrudate may be powder mixtures leaving the extruder. Hence, at the end the pharmaceutical extrudate comprise a desired cross-section. Furthermore, the pharmaceutical extrudate comprises a homogeneously distributed and dosed API content.
Hence, by having the pharmaceutical extrudate comprising the desired cross-section, tablets or other pharmaceutical products may be produced having an exact dosis of the API.
The extrusion material may consist of a solid powder or powdery material, respectively, and may be fed by a feeder, for example by a loss-in-weight feeder, to the feeding section of the screw extruder device. The extrusion material may be melt in a melting section of the screw extruder device while being transported with the extruder screw.
The extrusion material may be for example a mixture of Copovidone/Povidone (e.g., in a ration of Copovidone/Povidone = 80:20). The raw material may be solid powder with the copovidone/povidone pre-mix.
Furthermore, the extrusion material may consist of the following substances or mixtures thereof:
Ammonio methacrylate copolymer Poly (dimethylaminoethylmethacrylate-comethacrylicesters); Soluplus; Poly methyl acrylate-co-methyl; methacrylate-co-methacrylic acid 7:3:1; Poly methacrylic acid-co-methylmethacrylate 1:2; Hydroxypropyl cellulose; Ethyl cellulose; Cellulose acetate butyrate; Cellulose Acetate Phthalate; Poly ethylene oxide; Poly ethylene glycol; Poly vinyl pyrrolidone; Poly vinyl acetate; Hydroxypropyl Methylcellulose Phthalate; Polyvinylpyrrolidone-co-vinyl acetate; Hydroxypropyl Methylcellulose; Hydroxypropyl Methylcellulose Acetate; Succinate; Poly lactide-co-glycolide;
Polyvinyl Alcohol; Chitosan Lactate Sea; Pectin; Carbomer; Polycarbophil; Poly(ethylene-co-vinyl acetate); Polyethylene; Poly(vinyl acetate-co-methacrylic acid); Epoxy resin containing secondary amine; Polycaprolactone; Carnauba Wax; Ethylene-vinyl acetate copolymer; Glyceryl Palmitostearate; Hydrogenated Castor & Soybean Oil; Microcrystalline Wax; Corn Starch; Maltodextrin; Pregelatinized Starch; Isomalt; Potato Starch; Citric Acid; Sodium Bicarbonate; Methacrylic acid copolymer type C; Chitosan; Xanthan gum; Agar; Povidone; Lactose; Microcrystalline cellulose; Dibasic calcium phophate
The extrusion liquid may be in a liquid state and may have a certain viscosity. The viscosity of the extrusion liquid may be in an exemplary embodiment lower than the viscosity of the extrusion material. In an exemplary embodiment, the extrusion liquid and/or in particular the carrier solution has a viscosity of aproximately 0,5 Pa-s to aproximately 10 Pa-s, in particular aproximately 0,9 Pa-s to aproximately 1,1 Pa-s.
The extrusion liquid may be a suspension or a melt, wherein the carrier solution is a liquid in which solid API particles are inserted and homogenously distributed. The extrusion liquid is for example a suspension of API particles, an API solution or a melted API.
According to a further exemplary embodiment, the pumped predetermined volumetric flow rate of the extrusion liquid is approximately 5 ml/h, in particular approximately 40 ml/h to approximately 110 ml/h.
The API is solid and comprises particles having for example a particle size of approximately 15 pm (Micrometer) to 25 pm, in particular 22 pm to 23 pm. In an exemplary embodiment the particle size is 22.99±0.236 pm.
Alternatively, the extrusion liquid may be a solution which is a homogeneous mixture composed of only one phase. Hence, the API as a solute is dissolved in the carrier solution functioning as a solvent. The viscosity of the carrier solution defines the overall viscosity of the extrusion liquid. Summarizing, the extrusion liquid may consisting of suspended API particles, dissolved API and/or melted API.
According to an exemplary embodiment the active pharmaceutical ingredient (API) is selected from the group consisting of Ibuprofen or other pharmaceutical substances e.g. of biopharmaceutics classification BCS II.
Furthermore, the API may consist of the following substances or mixtures thereof:
Alprazolam; Amiloride hydrochloride; Astemizole; Atropine methonitrate; Atropine sulphate; Benzhexol hydrochloride; Bromhexine hydrochloride; Bromocriptine mesylate; Buprenorphine hydrochloride; Busulphan; Carbimazole; Chlorpheniramine maleate; Clonidine hydrochloride; Colchicine; Cyproheptadine hydrochloride; Dexamethasone; Diazepam; Dienoestrol; Digitoxin; Digoxin; Dydrogesterone; Ergometrine maleate; Ergotamine tartrate; Ethinyloestradiol; Fludrocortisone acetate; Fluphenazine hydrochloride; Glibenclamide; Haloperidol; Melphalan; Methadone hydrochloride; Methylergometrine maleate; Nicoumalone; Nitrazepam; Norethisterone; Norgestrel; Prednisolone; Prazosin; Salbutamol; Thyroxine sodium; Timolol maleate; Triamcinolone; Goserelin Acetate; Etonogestrel; Griseofulvin; composition of Etonogestrel, Ethinyl and Estradiol; Ritonavir; Ritonavir/Lopinavir; Vildagliptin/Metformin HCI; Azythromycin;
Dexamethasone; Fenofibrate; Anacetrapib; Atherosclerosis; Posaconazole;
According to an exemplary embodiment the carrier solution comprises polyethylene glycol (PEG), wherein the carrier solution has in particular a mass fraction of approximately 35% polyethylene glycol and approximately 65 % distilled water. The molecular weight of PEG and its concentration may dictate the viscosity of the carrier solution. The viscosity may be tuned to avoid the sedimentation of API particles in the pumping system.
Polyethylene glycol may be used as a thickener. There are PEG compositions with different molecular weights available (a parameter that affect viscosity in addition to PEG concentration). PEG is a pharmaceutical ingredient which is also soluble in water and in organic solvents.
Furthermore, the carrier solution may consist of the following substances or mixtures thereof:
Polyvinyl; caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; Polyethylene oxide; Poly(vinyl pyrrolidone), Polyvinylpyrrolidonecovinyl acetate; Poly(dimethylaminoethylmethacrylateco-methacrylic esters); Hydroxypropylmethylcellulose acetate succinate; Hydroxypropyl cellulose; Hydroxypropyl methylcellulose; Polyehtylene glycol; Polyvinyl alcohol-polyethylene glycol copolymer; Poly (lactic-co-glycolicacid) (PLGA); Cyclodextrin; Poloxamer; Chitosan.
According to an exemplary embodiment the density of carrier solution is between approximately 0.9 to approximately 3 gr/ml.
According to the present invention, liquids and suspensions can be fed highly accurate even at low flow rates, down to the range of microliters per hour. Thus, if the API can be suspended in an anti-solvent (or if the API has poor solubility) and if an anti-solvent (e.g. the carrier solution) can be removed in the process, low-dose feeding of APIs to the extrusion material can be accurately carried out via feeding a suspension instead of a powder.
By the present invention, the e.g. suspension of the extruder liquid is dosed to accurately feed an API at a controlled feed rate to the extrusion material in the extruder device. The carrier solution may be later on removed in situ (i.e., within the extruder device, e.g. in the mixing section) via devolatilization. The mixing capability of extruder device is then further used to create API low-dosed pharmaceutical extrudates with a high accuracy for further processing.
The approach of the present invention has the advantage that APIs with a poor solubility can be simply suspended in aqueous media (the carrier solution) and easily feed into the extrusion material within an (hot melt) extruder device or a continuous wet granulation in a twin-screw extruder device.
According to a further exemplary embodiment, before the step of pumping the extrusion fluid with a predetermined volumetric flow rate, the carrier solution is mixed with a dosed quantity of the active pharmaceutical ingredient to produce the extrusion liquid. For the mixing, e.g., Turrax high-shear mixer may be used.
According to a further exemplary embodiment, the carrier solution is evaporated out of the produced pharmaceutical extrudate after the step of mixing the extrusion liquid with the extrusion material. Therefore, the screw extruder device may have ventilation holes along the mixing section. Furthermore, a ventilator may be arranged for controlling the evaporation of the extrusion liquid.
In the following advantageous temperature ranges of sections and materials of the extrusion device and method steps are shown:
According to a further exemplary embodiment the extrusion material is heated in the feeding section such that the temperature of the extrusion material has approximately 75° C to approximately 85° C.
According to a further exemplary embodiment the extrusion material is heated in a melting section of the screw extruder device such that the temperature of the extrusion material has approximately 135° C to approximately 145° C.
According to a further exemplary embodiment the produced pharmaceutical extrudate is heated in the mixing section such that the temperature of the produced pharmaceutical extrudate has approximately 135° C to approximately 145° C.
According to a further exemplary embodiment the produced pharmaceutical extrudate is heated in the output section such that the temperature of the produced pharmaceutical extrudate has approximately 135° C to approximately 145° C.
According to a further aspect of the present invention, a production system for producing (e.g. by the method described above) a pharmaceutical extrudate comprising an active pharmaceutical ingredient is presented. The production system comprises a screw extruder device (single screw or double screw extruder) for conveying an extrusion material by an extruder screw of the screw extruder device from a feeding section of the screw extruder device to an output section of the screw extruder device. A pump is provided to the system for pumping an extrusion liquid with a predetermined volumetric flow rate, wherein the extrusion liquid comprises a carrier solution in which a dosed quantity of the active pharmaceutical ingredient is mixed. The system further comprises an injection device for injecting and adding the extrusion liquid to the extrusion material within an injection section of the screw extruder device, wherein the screw extruder device comprises a mixing section for mixing the extrusion liquid with the extrusion material to produce the pharmaceutical extrudate. The screw extruder device comprises an output section for outputting the pharmaceutical extrudate.
By the present invention a method and a production system is presented which shows that feeding an API in suspension liquid (with a poor solubility or anti-solvent) to an hot melt extruder offers a simplified process (i.e. fewer unit operations - no pre-mixing of solids) with more possibilities for easy process control (i.e. control of volumetric flow of a suspension is much easier to achieve than gravimetric control of powder flow of cohesive powders). More importantly, there are no powder feeders necessary that are capable of consistently delivering the API powder into the HME at the low rates required to manufacture low content extrudates in a continuous manner.
By the present invention, the feeding of an aqueous suspension of sparingly soluble API (BCS II or BCS IV) particles to the HME constitutes an advantageous and straightforward manufacturing practice that yields low-dose products with excellent homogeneity. Due to the ability to accurately control liquid flow rate, the feeding rate of API can be performed with great accuracy. As an additional benefit, applying high shear (Turrax mixer) in the preparation of the dilute suspension mitigates the agglomeration phenomena of cohesive API.
It has to be noted that embodiments of the invention have been described with reference to different subject matters. In particular, some embodiments have been described with reference to apparatus type claims whereas other embodiments have been described with reference to method type claims. However, a person skilled in the art will gather from the above and the following description that, unless other notified, in addition to any combination of features belonging to one type of subject matter also any combination between features relating to different subject matters, in particular between features of the apparatus type claims and features of the method type claims is considered as to be disclosed with this application.
Brief Description of the Drawings
The aspects defined above and further aspects of the present invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to the examples of embodiment. The invention will be described in more detail hereinafter with reference to examples of embodiment but to which the invention is not limited.
Fig. 1 shows a schematical view of a production system according to an exemplary embodiment of the present invention; and
Fig. 2 shows a process chart of the method production system according to an exemplary embodiment.
Detailed Description of Exemplary Embodiments
The illustrations in the drawings are schematic. It is noted that in different figures similar or identical elements are provided with the same reference signs.
Fig. 1 shows a production system for producing a pharmaceutical extrudate 101 comprising an active pharmaceutical ingredient (API). The production system comprises a screw extruder device 100 (single screw or double screw extruder) for conveying an extrusion material by an extruder screw 102 of the screw extruder device 100 from a feeding section 103 of the screw extruder device 100 to an output section 108 of the screw extruder device 100. An extrusion liquid 109 is provided to the system for pumping the extrusion liquid 109 with a predetermined volumetric flow rate, wherein the extrusion liquid 109 comprises a carrier solution in which a dosed quantity of the API is mixed. The system further comprises an injection device 112 for adding and injecting the extrusion liquid 109 to the extrusion material within an injection section 106 of the screw extruder device 100, wherein the screw extruder device 100 comprises a mixing section 107 for mixing the extrusion liquid 109 with the extrusion material to produce the pharmaceutical extrudate 101. The screw extruder device 100 comprises the output section 108 for outputting the pharmaceutical extrudate 101.
The extruder screw 102 may be a single screw or a double screw comprising two transporting screws for transporting and mixing the extrusion material. The screw extruder device 100 further comprises a feeder unit 113 (for example by a loss-in-weight feeder) which feeds the extrusion material into the feeding section 103 of the screw extruder device 100.
Downstream of the feeding section 103 along the transport direction 114 a transition section 104 and a melting section 105 of the screw extruder device 100 are arranged. In the melting section 105, the extrusion material, which may be fed as granulate, is melted such that after leaving the melting section 105 a homogenous viscous extrusion material is formed.
Next, the extruder screw transports the extrusion material along the transport direction 114 to an injection section 106 of the screw extruder device 100, where the extrusion liquid 109 is injected, for example by an injection device 112. Downstream along the transport direction 114 of the injection section 106 the screw extruder device 100 comprises a mixing section 107. Along the mixing section 107 the extrusion liquid 109 is mixed with the extrusion material while being transported by the extruder screw 102.
During transportation along the mixing section 107, a constant and homogeneous mixing between the extrusion material and extrusion liquid 109 is achieved, because of the liquid phase of the extrusion liquid 109 which is mixed to the extrusion material.
The screw extruder device 100 may further comprise heating elements. For example, along the mixing section 107 the extrusion material and the extrusion liquid 109 can be heated such that the extrusion liquid 109 and in particular the carrier solution evaporates and the API remains within the extrusion material.
In the feeding section 103 extrusion material is heated in the feeding section such that the temperature of the extrusion material has approximately 75° C to approximately 85° C. In the melting section 105 of the screw extruder device 100 the extrusion material is heated such that the temperature of the extrusion material has 135° C to 145° C. In the mixing section the produced pharmaceutical extrudate 101 is heated such that the temperature of the produced pharmaceutical extrudate 101 has 135° C to 145° C. In the output section 108 the produced pharmaceutical extrudate 101 is heated such that the temperature of the produced pharmaceutical extrudate 101 has 135° C to 145° C.
At the output section 108 of the screw extruder device 100, the pharmaceutical extrudate 101 (consisting of the extrusion material and the extrusion liquid 109 or the extrusion material and the API, because the liquid part (e.g. the carrier solution) of the extrusion liquid is evaporated) is outputted by pressing the extrudate 101 through an extruder nozzle having a predefined cross-section. Hence, at the end the pharmaceutical extrudate 101 comprise a desired cross-section. Furthermore, the pharmaceutical extrudate 101 comprises a homogeneously distributed and dosed API content.
Hence, by having the pharmaceutical extrudate 101 comprising the desired cross-section, tablets or other pharmaceutical products may be produced having an exactly doses of the API.
The extrusion liquid 109 may be in a liquid state and may have a certain viscosity. The viscosity of the extrusion liquid is lower than the viscosity of the extrusion material and should be enough to prevent the sedimentation of particles in the piping of the pumping system. The extrusion liquid may be a suspension, wherein the carrier solution is a liquid in which solid API particles are inserted and homogenously distributed.
The extruder liquid 109 is dosed by the injection device 112 to accurately feed an API at a controlled feed rate to the extrusion material in the extruder device 100. The carrier solution may be later on removed in situ (i.e. within the extruder device 100, e.g. in the mixing section 107) via devolatilization. The mixing capability of extruder device is then further used to create API low-dosed pharmaceutical extrudates 101 with a high accuracy for further processing. APIs with a poor solubility can be simply suspended in an aqueous media (the carrier solution) and easily feed into the extrusion material within an (hot melt) extruder device or a continuous wet granulation in a twin-screw extruder device.
Before the step of pumping the extrusion fluid 109 with a predetermined volumetric flow rate into the extrusion material, the carrier solution is mixed with a dosed quantity of the active pharmaceutical ingredient (API) to produce the extrusion liquid 109. For the mixing an e.g. Turrax mixer 110 may be used.
The carrier solution is evaporated out of the produced pharmaceutical extrudate 101 after the step of mixing the extrusion liquid 109 with the extrusion material. Therefore, the screw extruder device 100 may have ventilation holes along the mixing section 107. Furthermore, a ventilator may be arranged for controlling the evaporation of the extrusion liquid 109.
Fig. 2 shows a process chart of essential method steps of the method for producing an pharmaceutical extrudate 101 comprising an active pharmaceutical ingredient.
In step 201 an extrusion material is conveyed by an extruder screw 102 of a screw extruder device 100 from a feeding section 103 of the screw extruder device 100 to an output section 108 of the screw extruder device 100.
In step 202 an extrusion liquid 109 is pumped with a predetermined volumetric flow rate, wherein the extrusion liquid 109 comprises a carrier solution in which a dosed quantity of the active pharmaceutical ingredient is mixed.
In Step 203, the extrusion liquid 109 is added to the extrusion material within an injection section 106 of the screw extruder device 100.
In Step 204, the extrusion liquid 109 is mixed with the extrusion material within a mixing section 107 of the screw extruder device 100 to produce the pharmaceutical extrudate 101.
In Step 205, the pharmaceutical extrudate 101 is outputted at the output section 108 of the screw extruder device 100.
In the following an experiment of the method for producing a pharmaceutical extrudate 101 comprising an active pharmaceutical ingredient is described:
The suspension extrusion liquid 109 comprising ibuprofen to be side-fed to a hot melt extruder device 100 has a higher viscosity to minimize sedimentation. Polyethylene Glycol (PEG) 20.000 as carrier solution was selected to prepare a viscous liquid since PEG is widely used for pharmaceuticals formulations. PEG 20.000 (35% w/w) was dissolved in distilled water (65%) resulting in viscosities of approximately 1 Pa-s with a density of 1.055 gr/ml. The density is important as a correction factor because the pump 111 is feeding by volume and the mass balance for API content considers the weight of API in the suspension extrusion liquid 109.
Then, a diluted suspension extrusion liquid 109 of Ibuprofen (1% w/w) was prepared in an Ultra turrax (at 9000 rpm) because high shear rates may be helpful to de-agglomerate the API in a highly viscous media. The actual concentration of suspension was 0,8999% ± 0,0212 instead of the intended 1% w/w of Ibuprofen. This was due to the fact that particles were entrained in the foam generated during intense mixing with the Turrax mixer.
The hot-melt extrusion of the screw extruder device runs were performed in a Coperion 18mm twin-screw extruder. The temperature of the e.g. nine compartments in a barrels was monitored and temperatures high enough to obtain low melt viscosities were selected. However, the temperature was kept below 157°C (which is the boiling point of Ibuprofen). The temperature in the first compartment, i.e. in the feeding section 103, was in the range 80-83°C, for the second compartment, i.e. in the transition section 104, in the range of 121-126°C and for the other compartments, i.e. for the melting section 105, the injection section 106, the mixing section 107 and the output section 108, the temperatures were in the range of 138°C-141°C. The solid powder of the extrusion material was fed with a loss-in-weight feeder (e.g. K-tron SFS-24; Type 24/12) at a rate of approximately 2-kg/hour. The Ibuprofen suspension extrusion liquid 109 was prepared in a vessel of a mixing device 110 agitated with a magnetic bar. The suspension extrusion liquid 109 was pumped by pump 111 either at 50 ml/hr or at 100 ml/hr into the injection section 106 of the extruder device 100, according to the desired API concentration in the extrudate 101. The dosing operation of the extrusion liquid 109 is critical for the content uniformity and a highly accurate and calibrated pump 111 (e.g. pump mzr-7205G, Hnp-mikrosystem) was used to feed the suspension extrusion liquid 109.
The extrusion operation was carried out for 15 minutes to ensure a steady state before collecting extrudates 101 for analysis. Then, extrudate samples 101 are collected and further extrudates 101 are collected for the next 25 minutes, every 5 minute intervals. Strands of extrudate 101 at the end of the extruder device 100 are cut manually and milled for content analysis.
For very low API content extrudate 101, a highly accurate analytical technique is critical for content uniformity assay. A HPLC analysis was performed using an e.g. an Agilent 1260 series Infinity HPLC system (Agilent, Waldbronn, Germany), equipped with an online degasser, quaternary pump, autosampler, thermostatted column compartment and UV-visible diode array detector. A Purospher® STAR RP-18 endcapped (150x4.6 mm; 5 pm) (Merck, Darmstadt, Germany) analytical column was used as stationary phase. Analysis was carried out under isocratic elution conditions using a mobile phase composed of acetonitrile (Sigma Aldrich)/ water (chromatography quality)/ 8.5 wt.% phosphoric acid (HPLC grade, VWR international, 670:325:5 v/v) at a flow rate of lmL/ min. Column temperature was set to 20 °C and an aliquot of 20pL of sample solution was injected into the HPLC system. UV-detection was performed at 231 nm over the run time of 7 minutes. Linearity of the method was tested in the range from 1.05 pg/mLto 15 pg/mL. Instrument repeatability and specificity with regard to blank solvent and excipients were investigated in the course of system suitability testing. Sample solutions were prepared by dissolving lOOmg of the milled extrudate in 100 mLof mobile phase.
The results are aimed to demonstrate the benefit of injecting the API in suspension extrusion liquid 109 into an HME 100 as a simplified and more easily controllable manufacturing set-up. Because it is complicated to feed a solid API powder with a gravimetric feeder at the required low rates, the inventive method and set-up for the manufacturing of low-dose extrudates 101 is compared with the traditional and conventional approach of solid premixing of APIs and subsequent extrusion. It is focused on two extricate properties: API mean concentration (assay) and content uniformity.
The results are shown in Table 1. In the first set of columns the results for the extrusion with liquid injection are presented for different screw speeds, followed by the characterization of the API-carrier pre-mix and by the results for the extrusion of the pre-mix without side-side feeding at 400 rpm. In the rows the expected API concentration, the measured mean concentration via HPLC and UV as well as the RSD of the samples with size of scrutiny of lOOmg are shown.
Table 1: Mean content and dose variability of extrudates prepared under different extrusion conditions and for the four 1-kg batches of physical blend.
The Mean concentration is defined as Mean concentration (wt %) = Concentration (pg/mL) * Volume (ml) / Extrudate Sample Weight (mg) *100/1000
The concentration (pg/mL) was measured with HPLC. SD (Standard deviation) =
Where x is the concentration of each sample and x is the average concentration of n samples.
The RSD mean concentration is defined as RSD mean concentration (%) = SD / Mean concentration (w %) * 100.
As can be seen from Table 1, feeding a suspension extrusion liquid 109 of API into a hot-melt extruder 100 yields products with a high content uniformity despite the very low mean concentration of API of less than 0.1%. As can be seen the RSD mean concentration is between 2.2% and 7.3%. Interesting is the fact that at higher screw speeds higher RSD mean concentrations are obtained. Mixing performance is highly affected by residence time, which is a function of the fill level in the screw sections and the flow rate.
As can be seen, the conventional dry pre-mix had a very good quality with an RSD between 0.7% and 4.1. The RSD of the corresponding material is thus also low, i.e., 3%.
As can be seen creating a low-dose material via suspension side feedings results in materials that are similar to the once produced by feeding a very-well mixed blend of API and excipients. While the RSD of extrudates manufactured via the HME of physical blends is 3%, the content uniformity of extrudates generated via injection of a suspension according to the present invention into the HME for identical extruder conditions is between 2.2% and 7.3% (Table 1).
Regarding the mean content of the extrudates, the difference between the expected mean content and the real one at low API content of extrudates is analyzed. In the case of extrusion of the physical blend, there is no significant difference between expected mean content and the real content (0.1% vs 0.0981% ± 0.0029%). In the feeding of API in suspensions according to the present invention, there is a trend to extrudates with mean concentrations slightly lower than expected. However, this difference was significant only in one case (Expected API content of 0.0213% and 200 rpm). When water is evaporated, the solid PEG remains in the extruded material which was affecting the mass (100 mg) of the API/excipient mixture for testing, effectively lowering the measured API concentration.
Summarising it is demonstrated that feeding API in a viscous suspension according to the present invention is a method to overcome the limitations of low-dose powder feeders and to enable the miniaturization of extrusion process and the continuous manufacturing of low dose extrudates (e.g.powdery materials).
It should be noted that the term "comprising" does not exclude other elements or steps and "a" or "an" does not exclude a plurality. Also elements described in association with different embodiments may be combined. It should also be noted that reference signs in the claims should not be construed as limiting the scope of the claims.
List of reference signs: 100 screw extruder device 101 pharmaceutical extrudate 102 extruder screw 103 feeding section 104 transition section 105 melting section 105 injection section 107 mixing section 108 output section 109 extrusion liquid 110 mixing device 111 pump 112 injection device 113 feeder unit 114 transport direction 201 conveying 202 pumping 203 adding 204 mixing 205 outputting

Claims (15)

CLAIMS:
1. Method for producing a pharmaceutical extrudate (101) comprising a low dose active pharmaceutical ingredient, the method comprising conveying an extrusion material by an extruder screw (102) of a screw extruder device (100) from a feeding section (103) of the screw extruder device (100) to an output section (108) of the screw extruder device (100), pumping an extrusion liquid (109) with a predetermined volumetric flow rate, wherein the extrusion liquid (109) comprises a carrier solution with a dosed quantity of the active pharmaceutical ingredient, adding the extrusion liquid (109) to the extrusion material within an injection section (106) of the screw extruder device (100), mixing the extrusion liquid (109) with the extrusion material within a mixing section (107) of the screw extruder device (100) to produce the pharmaceutical extrudate (101), and outputting the pharmaceutical extrudate (101) at the output section (108) of the screw extruder device (100).
2. Method according to claim 1, further comprising before the step of pumping the extrusion fluid mixing the carrier solution with a dosed quantity of the active pharmaceutical ingredient to produce the extrusion liquid (109).
3. Method according to claim 1 or 2, wherein the extrusion liquid (109) and/or the carrier solution has a viscosity of 0,5 Pa-s to 50 Pa-s, in particular 0,9 Pa-s to 1,1 Pa-s.
4. Method according to one of the claims 1 to 3, wherein the carrier solution comprises polyethylene glycol, wherein the carrier solution has in particular a mass fraction of 35% polyethylene glycol and 65 % distilled water.
5. Method according to claim 4, wherein the density of carrier solution is between 1,0 to 1,1 gr/ml.
6. Method according to claim one of the claims 1 to 5, wherein the active pharmaceutical ingredient is solid and comprises particles, wherein the extrusion liquid (109) is a suspension.
7. Method according to claim one of the claims 1 to 6, wherein the active pharmaceutical ingredient is Ibuprofen.
8. Method according to claim one of the claims 1 to 7, wherein the extrusion material is a copovidone/povidone pre-mix.
9. Method according to claim one of the claims 1 to 8, further comprising evaporating the carrier solution out of the produced pharmaceutical extrudate (101) after the step of mixing the extrusion liquid (109) with the extrusion material.
10. Method according to claim one of the claims 1 to 9, further comprising heating the extrusion material in the feeding section (103) such that the temperature of the extrusion material has 75° C to 85° C.
11. Method according to claim one of the claims 1 to 10, further comprising heating the extrusion material in a melting section (105) of the screw extruder device (100) such that the temperature of the extrusion material has 135° C to 145° C.
12. Method according to claim one of the claims 1 to 11, further comprising heating the produced pharmaceutical extrudate (101) in the mixing section (107) such that the temperature of the produced pharmaceutical extrudate(lOl) has 135° C to 145° C.
13. Method according to claim one of the claims 1 to 11, further comprising heating the produced pharmaceutical extrudate (101) in the output section (108) such that the temperature of the produced pharmaceutical extrudate (101) has 135° C to 145° C.
14. Method according to claim one of the claims 1 to 13, wherein the pumped predetermined volumetric flow rate of the extrusion liquid (109) is 40 ml/h to 110 ml/h.
15. Production system for producing an pharmaceutical extrudate (101) comprising an active pharmaceutical ingredient, the production system comprising a screw extruder device (100) for conveying an extrusion material by an extruder screw (102) of the screw extruder device (100) from a feeding section (103) of the screw extruder device (100) to an output section (108) of the screw extruder device (100), a pump (111) for pumping an extrusion liquid (109) with a predetermined volumetric flow rate, wherein the extrusion liquid (109) comprises a carrier solution in which a dosed quantity of the active pharmaceutical ingredient is mixed, and injection device for injecting the extrusion liquid (109) to the extrusion material within an injection section (106) of the screw extruder device (100), wherein the screw extruder device (100) comprises a mixing section (107) for mixing the extrusion liquid (109) with the extrusion material to produce the pharmaceutical extrudate (101), wherein the screw extruder device (100) comprises the output section (108) for outputting the pharmaceutical extrudate (101).
GB1512436.5A 2015-07-16 2015-07-16 Method and production system for producing a pharmaceutical extrudate comprising a low-dose active pharmaceutical ingredient Withdrawn GB2540400A (en)

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US20030099688A1 (en) * 2001-10-05 2003-05-29 Huber Gordon R. Animal feeds including heartworm-prevention drugs
FR2882663A1 (en) * 2005-03-07 2006-09-08 Arolab Spherical granule maker, e.g. for pharmaceutical or food products, has extruder with single compression screw and segments of variable pitch and direction

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WO2019043614A1 (en) * 2017-08-31 2019-03-07 Novartis Ag Method for preparing granules
CN111194211A (en) * 2017-08-31 2020-05-22 诺华股份有限公司 Process for preparing granules
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