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WO2006026844A1 - Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture - Google Patents

Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture 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
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Prior art keywords
hormone
composition
human body
delayed release
manufacture
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Ceased
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PCT/BR2005/000183
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French (fr)
Inventor
Ademar Benévolo LUGÃO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biolab Sanus Farmaceutica Ltda
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Biolab Sanus Farmaceutica Ltda
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Application filed by Biolab Sanus Farmaceutica Ltda filed Critical Biolab Sanus Farmaceutica Ltda
Priority to MX2007002845A priority Critical patent/MX2007002845A/en
Publication of WO2006026844A1 publication Critical patent/WO2006026844A1/en
Anticipated expiration legal-status Critical
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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
    • A61K9/0012—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular 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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  • 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)
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Abstract

Hormone delayed release composition, use of the composition, hormone delayed release device, process for the manufacture of hormone delayed release device and methods for the treatment of conditions or dysfunctions. The present invention refers to a hormone delayed release composition within the human body, more particularly to a non-biodegradable biocompatible composition comprising a polymer matrix selected from the group of polyorgonomiloxones or ethylene vinyl acetate crosslinked by ionizing radiation wherein a hormone is dispersed. In other aspects, the present invention refers to the use of said composition to obtain 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.

Description

Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture. »
FIELD OF THE INVENTION
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. In other aspects, 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.
BACKGROUND THE INVENTION Means for the controlled release of drugs within the human body are known, in which active principles and pharmaceutical preparations are mixed with pharmaceutically appropriate vehicles and inserted in the patient bodies. While in the organism, the vehicle disintegrates or slowly biodegrades, allowing slow drug release. However, currently used vehicles not always correspond to satisfactory biological and pharmaceutical results. This is not the case of the present invention.
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. However, 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.
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.
It can be verified in the prior art that, no matter the way on how the material acting as a matrix is placed to release the drug dispersed therein, its polymerization or crosslinking is always carried out hot or catalytically in the presence of solvents. In any of these alternatives, there is loss to the performance of the drug dispenser, i.e.:
- when heat is involved in crosslinking, there is a higher degradation of the polymer or of the active principle dispersed therein; - in case of catalytic crosslinking, there is a higher contamination by solvents and catalysts eventually retained in the polymer, thus requiring later purification stages.
Therefore, 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. Bhattacharya, Radiation and Industrial Polymers, Prog. Polym. Sci. 25 (2000) pages 371 -401 ). Furthermore, hormones are not submitted to inactivation or decomposition temperatures, thus preserving their potential of action and avoiding the formation of toxic byproducts.
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.
In another aspect, 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.
DESCRIPTION OF THE INVENTION
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. As biocompatible polymers, 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.
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.
Particularly, 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, β-estradiol is particularly used.
The 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. Such 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;
(ii) Cold molding said mixture into the desired shape; (iii) Cold de-molding;
(iv) Packing the obtained product;
(v) Exposing the packed product to enough ionizing radiation to crosslink the polymer and sterilize the packed product. Gamma radiation or beam of electrons is particularly used. One of the advantages of irradiating the already packed product is the fact that the polymeric material composing the polymeric matrix is crosslinked simultaneously to the sterilization of the already packed device of the present invention.
Within embodiment alternatives, there are optional steps which may be a part of the process of the invention, such as:
- to expose the molded mixture of step (ii) above to ionizing radiation, for previous crosslinking and to already start sterilization;
- after demolding of step (iii), coat the material with an outside layer, particularly of biocompatible polymeric material, optionally with the same polymeric material of item (i).
Particularly, 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.
EXAMPLE IN VIVOTESΎ
Cylindrically-shaped implants with 2 mm diameter and 20 mm long constituted by polydimethylsiloxane, 50 mg of 17 β-estradiol and barium sulfate as the radio marker were prepared. For implant injection, 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
I of the implant withdrawal
I i post-surgery
dally collection weekly collection
The collected samples were centrifuged at 1000 rotations for 5 minutes. Supernatant (plasma) was separated and stocked at -200C in
Eppendorf tubes until assays were made. Subsequently, results of the samples corresponding to the average release of 17-β-estradiol during the assay period were plotted in a graph.

Claims

1 . 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.
2. COMPOSITION, according to Claim 1 , characterized in that said biocompatible polymer is chosen from polyorganosiloxanes, particularly polydialkylsiloxanes, such as polydimethylsiloxanes, and ethylene-vinyl acetate copolymer.
3. COMPOSITION, according to Claim 1 , characterized in that said hormone is pharmaceutically acceptable, able to be delayed released by diffusion being dispersed within said polymeric matrix.
4. COMPOSITION, according to Claim 1 , characterized in that said hormone is chosen among estrogens.
5. COMPOSITION, according to Claim 1 , characterized in that said hormone is an estrogen, particularly β-estradiol.
6. COMPOSITION, according to Claim 1 , characterized in that it contains up to about 80% by weight of inert fillers.
7. COMPOSITION, according to Claim 1 , characterized in that it contains a radio-opaque marker, particularly above 0.1 % by weight, more particularly between 0.1 % and 2%.
8. USE OF THE COMPOSITION, as described in Claims 1 to 7, characterized in that it is for the manufacture of a hormone delayed release device within the human body.
9. USE, according to Claim 8, characterized in that said device is a subcutaneous implant.
10. HORMONE DELAYED RELEASE DEVICE, within the human body, characterized in that it comprises the composition described W 2
Claims 1 to 7.
11. DEVICE, according to Claim 10, characterized in that it comprises an outside layer made of the same material of said polymeric matrix, or of a different material.
12. DEVICE, according to Claim 10, characterized in that said device presents geometry chosen from bands, sticks, cylinders or tubes.
13. DEVICE, according to Claim 12, characterized in that said device has the shape of a tube.
14. DEVICE, according to claim 12, characterized in that said device has the shape of an about 1 cm to about 12 cm long stick with about 0.3 mm to about 10 mm diameter.
15. DEVICE, according to claim 14, characterized in that said device has the shape of an about 1 cm to about 4 cm long stick with about 2 mm to about 4 mm diameter.
16. PROCESS FOR THE MANUFACTURE OF HORMONE
DELAYED RELEASE DEVICE, within the human body, as described in Claims 10 to 15, characterized in that it comprises the steps of (i) mixing one ore more substantially non-biodegradable biocompatible polymers with one or more hormones and additives, if any; (ii) cold molding said mixture into the desired shape; (iii) cold de-molding; (iv) packing the obtained product; (v) exposing the packed product to enough ionizing radiation to crosslink the polymer and sterilize the packed product.
17. PROCESS, according to Claim 16, characterized in that said ionizing radiation is chosen between gamma radiation and beam of electrons.
18. PROCESS, according to Claim 16, characterized in that after the step (ii) of cold molding the mixture, the mixture is exposed to ionizing radiation.
19. PROCESS, according to Claim 16, characterized in that after the step (iii) of cold demolding, the material is coated with an outside layer, particularly of biocompatible polymeric material, optionally the same polymeric material of item (i).
20. METHOD FOR THE TREATMENT OF CONDITIONS OR DYSFUNCTIONS, of the human body, characterized in that it is by inserting and maintaining the composition as described in Claims 1 to 8, inside the human body for enough time for said hormone to be appropriately released within the body.
21. METHOD FOR THE TREATMENT OF CONDITIONS OR DYSFUNCTIONS, of the human body, characterized in that it is by inserting and maintaining the device as described in Claims 10 to 15, inside the human body for enough time for said hormone to be appropriately released within the body.
PCT/BR2005/000183 2004-09-09 2005-09-09 Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture Ceased WO2006026844A1 (en)

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BRPI0406247-7 2004-09-09

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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)

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Publication number Priority date Publication date Assignee Title
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