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WO2006026844A1 - Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication - Google Patents

Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication Download PDF

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Publication number
WO2006026844A1
WO2006026844A1 PCT/BR2005/000183 BR2005000183W WO2006026844A1 WO 2006026844 A1 WO2006026844 A1 WO 2006026844A1 BR 2005000183 W BR2005000183 W BR 2005000183W WO 2006026844 A1 WO2006026844 A1 WO 2006026844A1
Authority
WO
WIPO (PCT)
Prior art keywords
hormone
composition
human body
delayed release
manufacture
Prior art date
Application number
PCT/BR2005/000183
Other languages
English (en)
Inventor
Ademar Benévolo LUGÃO
Original Assignee
Biolab Sanus Farmacêutica Ltda.
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
Family has litigation
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Application filed by Biolab Sanus Farmacêutica Ltda. filed Critical Biolab Sanus Farmacêutica Ltda.
Priority to MX2007002845A priority Critical patent/MX2007002845A/es
Publication of WO2006026844A1 publication Critical patent/WO2006026844A1/fr

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture. »
  • the present invention refers to an improvement in hormone delayed release compositions within the human body, more particularly to a non ⁇ biodegradable biocompatible composition comprising a polymeric matrix crosslinked by ionizing radiation wherein a hormone is dispersed.
  • the present invention refers to the use of said composition to obtain a hormone delayed release device, to the process for the manufacture of said device, and to a method for the treatment of conditions or dysfunctions of the human body.
  • Another common mean to obtain delayed release is to encapsulate the active principle with biodegradable coatings, such as cellulose derivatives, starches and polysaccharides, a technical widely used for the analgesics controlled release.
  • biodegradable coatings such as cellulose derivatives, starches and polysaccharides
  • said encapsulated drug presents problems for its use, such as difficulty to be located within the body and removed - for example, in case of allergic reactions - besides the difficulty of obtaining an appropriate distribution of the coating thickness (in order to provide the desired release) and the latency period of the coated agent in the gastrointestinal treat is relatively short, causing low efficacy of its use for delayed release. This is not the case of the present invention.
  • US 3,279,996 refers to a slow drug release device, typically a silicon rubber matrix, i.e., a high or room temperature vulcanized organopolysiloxane (called RTV, “Room Temperature Vulcanizing”), wherein the drug is dispersed.
  • RTV room temperature vulcanized organopolysiloxane
  • US 3,948,254 refers to a vehicle containing a drug and an outside layer for said vehicle, both permeable to the passage of the drug to be released.
  • the rate of passage of the drug through the outside layer is lower than the rate of passage of the drug through the solid vehicle, by diffusion.
  • the vehicle is typically a polyorganosiloxane, obtained by traditional processes.
  • US 4,957,119 refers to an implant of polymeric material for slow releasing of a contraceptive agent.
  • the polymeric material is made of a core and an outside layer, both made of ethylene/vinyl acetate copolymer, separated by a membrane.
  • the device is obtained by coextrusion, and therefore, under high temperature.
  • US 6,117,442 refers to a controlled rate release device for a therapeutically active agent, comprising a core of fluorinated siloxane (3,3,3- trifluoropropyl groups linked to the silicon atoms of the siloxane group) and an elastomeric covering membrane.
  • the device is obtained by traditional processes.
  • catalytic systems crosslinkable polymers in the presence of solvents or under high temperatures, suffer loss of their mechanic and chemical properties, additionally generating oligomers which damage their use for subcutaneous application.
  • the present invention provides a polymeric matrix and a device which are less susceptible to the problems of the prior art, in a simple way and with an advantageous cost-benefit ratio.
  • This is due to the use of ionizing radiation to crosslink the polymer acting as a matrix for the hormone controlled release to be released, not depending on high temperatures, or the presence of catalysts or solvents.
  • the cold cure or crosslinking of polymeric materials by means of the use of ionizing radiation is advantageous since it does not depend on the presence of catalysts or additives and may be made under any temperature.
  • the lack of catalysts and chemical initiators assures to obtain much purer products not requiring expensive purification stages, besides avoiding the risk of local overheating causing strong polymer degradation, which could generate toxic byproducts (A.
  • the dosage regimen for the hormones contained in the devices of the present invention varies according to known factors, such as the pharmacodynamic characteristics of the particular agent; the species, age, sex, health, medical conditions, and weight of the patient; the nature and extent of the symptoms; the sort of concurrent treatment; and the desired effect.
  • a physician knows how to determine and prescribe the quantity and efficient rate of releasing of the hormone to be administered to the patient.
  • Ionizing radiation as used in the invention typically gamma radiation or beam of electrons, fully penetrates in the body of the polymeric matrix, just reacting with electrons, not providing the formation of isotopes. It can be verified that the use of other types of radiation, like UV, provide substantially surface polymerization and are not an object of the present invention.
  • the base polymer of the polymeric matrix is purer, not requiring expensive purification stages.
  • the present invention therefore refers to a hormone delayed release composition, characterized in that it comprises a non-biodegradable biocompatible polymer matrix, crosslinked by ionizing radiation, wherein said matrix comprises one or more hormones dispersed therein.
  • the invention refers to the use of said composition characterized in that it is for the manufacture of a device for hormones controlled release within the human body.
  • the present invention also refers to a method for the treatment of conditions or dysfunctions, characterized in that it is by inserting and maintaining said composition inside the human body for enough time for said hormone to be delayed released within the body.
  • a first object of the present invention is a hormone delayed release composition characterized in that it comprises (1 ) a non-biodegradable biocompatible polymeric matrix, crosslinked by means of ionizing radiation, and (2) a hormone dispersed in said polymeric matrix.
  • This composition makes use of the diffusion phenomenon, according to which an active principle migrates through the polymeric matrix under delayed and/or controlled rate.
  • the polymeric matrix of the present invention may comprise any substantially non-biodegradable biocompatible polymer of natural or synthetic origin. As known by a person skilled in the art, polymers with high molecular mass are generally biocompatible due to their chemical inertia. Said matrix provides important chemical and mechanical properties and allows optimized diffusion of the active principle contained therein to the site of absorption inside the user body.
  • polyorganosiloxanes in general particularly polydialkylsiloxanes, such as polydimethylsiloxanes and EVA (ethylene and vinyl acetate copolymer) can be recited, with no exclusion of any other, provided it is crosslinkable by ionizing radiation.
  • polydialkylsiloxanes such as polydimethylsiloxanes and EVA (ethylene and vinyl acetate copolymer)
  • EVA ethylene and vinyl acetate copolymer
  • the hormones which may be used by the invention are pharmaceutically acceptable ones, which may be delayed released, being dispersed within the polymeric matrix. They may be available under liquid or solid form, and the latter one is preferred. A particular example, are estrogens, efficient for the treatment of existing conditions in the animal body, particularly humans, or in the body fluids.
  • the hormone releasing rate will depend on the affinity of each matrix-active principle set, wherein the release rate of each set should be verified, as the known by a person skilled in the art.
  • the hormone may be loaded to the matrix until a limit concentration allowing its crosslinking and until the obtainment of appropriated mechanical properties. These limits, therefore, depend on each matrix and each active principle, as determined by a person skilled in the art.
  • the hormone is an estrogen used, for example, for hormone reposition, vaginitis treatment, prostate cancer therapy and some cases of breast cancer, or as a contraceptive, ⁇ -estradiol is particularly used.
  • composition of the present invention may also comprise other ingredients, such as inert fillers present in the polymeric matrix, under values of up to about 80% by weight.
  • the composition of the present invention may also optionally comprise a radio-opaque marker, i.e. visible to X-ray, in order to facilitate its location, e.g. when used in implant, in case its location is required after accidental migration from the site of placement.
  • the marker may be any compound known in the art, e.g. barium sulfate.
  • the amount of barium sulfate is particularly of more than 0.1 % by weight in relation to the rest of the composition, which is enough to make the device visible to X-ray, preferably between 0.1% and 2% by weight.
  • a second object of the present invention is the use of said composition for the manufacture of a hormone delayed release device within the human body, e.g. by subcutaneous implantation, or an insert to the human body acting as an artificial gland.
  • Another object of the present invention is hormone delayed release devices within the human body, which comprise the composition containing the polymeric matrix as disclosed.
  • the release device of the present invention may also optionally comprise an outside layer to improve the control of the active principle release rate.
  • an outside layer may be made of the same material as the polymeric matrix, or a different material. A person skilled in the art knows how to establish the measurements of said outside layer, based on available data in the prior art.
  • the release device of the present invention may present various geometries, such as bands with various crosswise sections, sticks, cylinders and spherical tubes, preferably spherical tubes. It has particularly the shape of a
  • 1-12 cm long stick preferably 2 to 4 cm and about 0.3 to 10 mm diameter, preferably 2 to 4 mm.
  • Another object of the present invention is a process for the manufacture of a device for hormone delayed release within the human body. Said process comprises the steps of: (i) Mixing one or more substantially non-biodegradable biocompatible polymers with one or more hormones and additives, if any;
  • step (ii) to expose the molded mixture of step (ii) above to ionizing radiation, for previous crosslinking and to already start sterilization;
  • step (iii) coat the material with an outside layer, particularly of biocompatible polymeric material, optionally with the same polymeric material of item (i).
  • the polymer of item (i) and the optional outside layer are made of polyorganosiloxane, more particularly polydimethylsiloxane.
  • a further object of the present invention is a method for the treatment of conditions or dysfunctions of the human body, characterized in that it uses the device as obtained according to the process described above, particularly as a subcutaneous implant.
  • the device of the invention may also be used for the treatment of conditions or dysfunctions as an anal, vaginal, oral, nasal or any other insert. Below an example of use of the device of the present invention is presented, but its mention does not bring any limitation than the ones presented in the claims as further disclosed below.
  • Cylindrically-shaped implants with 2 mm diameter and 20 mm long constituted by polydimethylsiloxane, 50 mg of 17 ⁇ -estradiol and barium sulfate as the radio marker were prepared.
  • Crestar ® dischargeable heparinized syringes were used, and the blood should be obtained by means of venous puncture with a 25 x 8 needle.
  • An implant was subcutaneously injected in a mammal into its upper dorsal region, between pallets to facilitate application. That region was depilated.
  • Samples of blood from the mamma! were collected a few days before inserting the implant and for a period of about 17 days after its placement. After this period, ten other samples were collected within weekly intervals.
  • the sample as collected before the placement of the implant serves to confirm the non-existence of circulating estradiol. ovarectomy placement

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention a trait à une composition hormonale à libération différée, à l'utilisation de la composition, à un dispositif de libération différée d'hormones, à un procédé de fabrication de dispositif de libération différée d'hormones et à des procédés pour le traitement de conditions ou de dysfonctionnements. La présente invention a trait à une composition hormonale à libération différée dans l'organisme humain, plus particulièrement à une composition biocompatible non biodégradable comprenant une matrice à base de polymère choisi parmi le groupe de polyorganosiloxanes ou d'éthylène-acétate de vinyle réticulé par rayonnement ionisant dans laquelle est dispersée une hormone. Dans d'autres modes de réalisation, la présente invention a trait à l'utilisation de ladite composition pour obtenir un dispositif de libération différée d'hormones, au procédé pour la fabrication dudit dispositif et à un procédé pour le traitement de conditions ou de dysfonctionnement de l'organisme humain.
PCT/BR2005/000183 2004-09-09 2005-09-09 Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication WO2006026844A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
MX2007002845A MX2007002845A (es) 2004-09-09 2005-09-09 Composiciones de hormonas de liberacion prolongada sobre la base de poliorganosiloxanos o etilenvinilacetato y su respectivo proceso para su manufactura.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0406247-7 2004-09-09
BR406247 2004-09-09

Publications (1)

Publication Number Publication Date
WO2006026844A1 true WO2006026844A1 (fr) 2006-03-16

Family

ID=36036036

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2005/000183 WO2006026844A1 (fr) 2004-09-09 2005-09-09 Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication

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WO (1) WO2006026844A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9220692B2 (en) 2010-05-05 2015-12-29 Teva Women's Health, Inc. Methods of reducing symptoms in subjects using single dosage forms with tapering release rates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4012497A (en) * 1974-09-24 1977-03-15 Schering Aktiengesellschaft Drug excipient of silicone rubber
EP0970704A1 (fr) * 1998-07-02 2000-01-12 The Population Council, Inc. Implant avec un noyau en silicone pour une libération prolongée d'androgène
US20040009222A1 (en) * 2002-05-07 2004-01-15 Control Delivery Systems, Inc. Processes for forming a drug delivery device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4012497A (en) * 1974-09-24 1977-03-15 Schering Aktiengesellschaft Drug excipient of silicone rubber
EP0970704A1 (fr) * 1998-07-02 2000-01-12 The Population Council, Inc. Implant avec un noyau en silicone pour une libération prolongée d'androgène
US20040009222A1 (en) * 2002-05-07 2004-01-15 Control Delivery Systems, Inc. Processes for forming a drug delivery device

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9220692B2 (en) 2010-05-05 2015-12-29 Teva Women's Health, Inc. Methods of reducing symptoms in subjects using single dosage forms with tapering release rates

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