Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins

Definitions

• the subject of the present invention is a new transdermal device or matrix system for the sustained release of an estrogenic component and / or of a progestogen component, said device being formed of a support and an adhesive matrix, which is composed of 'a triblock copolymer having ABA units of the poly (styrene-isoprene-styrene) type [abbreviated as SIS], and in which said estrogen component and / or said progestin component, propyleneglycol laurate associated with an N- derivative, are dissolved alkyl-2-pyrrol ⁇ done and a copolymer of vinyl acetate and N-v ⁇ nyl-2-pyrrol ⁇ done [abbreviated VA / VP]
• the invention also relates to a process for the preparation of said matrix system and its use in therapeutic art.
• the estrogenic components and the progestin components are products which hardly pass the skin barrier.
• the quantities released of these active ingredients to obtain the desired therapeutic effect are generally low compared to the initial quantities present in the transdermal devices which results in obtaining low yields. This leads to the use of a quantity of hormone (s) very excess compared to that actually consumed.
• hormone s
• the estrogenic components and the progestogenic components are products which are poorly soluble in the polymers used in the so-called matrix transdermal systems.
• VA / VP N-vinyl-2-pyrrohdone
• a method is recommended for the preparation of said transdermal matrix system, said method being characterized in that it comprises the following steps which consist either of,
• VA / VP at a temperature between 80 and 110 ° C., then homogenize the resulting mixture, ( ⁇ ) incorporate into the homogeneous mixture thus obtained, at least one hormone chosen from the group consisting of the estrogenic components and the progestogen components, then homogenize the resulting mixture; ( ⁇ ) coat the homogeneous mixture thus obtained, at a temperature between 80 and 130 ° C, on a temporary non-stick support so as to obtain a coating on said support.
• VA / VP an N-alkyl-2-pyrrolidone and propylene glycol laurate then homogenize the resulting mixture
• transdermal matrix system is also recommended for obtaining a medicament intended for therapeutic use with regard to the symptoms of menopause or osteoporosis.
• FIGS. 1 to 5 represent the yield (R), expressed in%, in Es (17 ⁇ -oestrad ⁇ ol) or NETA (norethisterone acetate) as a function of time (t), expressed in hours More precisely in these drawings, FIG.
• poly (ABA) triblock copolymer of the poly (styrene- ⁇ sopré ⁇ e- styrene) type [abbreviated: poly (SIS)] is meant HERE a poly (SIS) material having a styrene content of between 14 and 50% by weight relative to the weight of said poly (SIS) is preferably used among the products well known to those skilled in the art that sold by DEXCO company under the name VECTOR ® 421 1 D having a styrene content of 29% by weight by weight of said poly (SIS) or mixtures of these poly (SIS)
• Poly (SIS) containing a mixture of poly (ABA) triblock copolymers and poly (AB) diblock copolymers of the poly (styrene-isoprene) type can also be used.
• Such products are well known to those skilled in the art. example marketed by the companies SHELL and EXXON CHEMICAL respectively under the names KRATON ® D and VECTOR ® 4113 or VECTOR ® 4114 By copolymer of vinyl acetate and N-v ⁇ nyl-2-pyrrol ⁇ done
• VA / PV HERE is understood to mean a copolymer having an acetate content of vinyl of between 30 and 70% by weight relative to the weight of said copolymer
• Such products are well known for their use as film-forming agents in aerosols and are for example marketed under the name "PVP / VA” by the company GAF CORPORATION in the form powder for the "PVP / VA-S” series, or solution in ethanol or isopropanol respectively for the "PVP / VA-E” and "PVP / VA-1" series or by the company BASF under the name Kollidon VA
• VA / VP copolymers sold respectively under the names "PVP / VA-S-630" (which has a content of 40% by weight of vinyl acetate) and Kollidon VA 64 (which has a content of 37.7% by weight of vinyl acetate)
• tackifying resins or tackifiers
• the resins generally used in the field of adhesives such as polyterpene or modified terpene resins, hydrogenated rosin resins, polymerized rosin resins, rosin ester resins, hydrocarbon resins, ete
• hydrocarbon resins such as those sold by Exxon Chemical under the name Escorez ® (ECR ® resins such as 385, 179A and ECR ®
• estradiol in particular the mono- and diesters of estradiol, such as for example 17-acetate estradiol, 3, Estradiol 17-acetate, estradiol 3- benzoate, estradiol 17-undecanoate, alkyl derivatives position 17 of estradiol such as ethmyloestradiol, 3-isopropylsulfonate ethinyloestradiol, methyloestradiol, quinestrol, mestranol and, if appropriate, their mixtures
• progestogen components which are suitable according to the invention, mention may in particular be made of progesterone, medrogesterone and their derivatives (in particular 17-hydroxyprogesterone acetate, medroxyprogesterone acetate), norethisterone and its derivatives, in particular acetate of 17-noreth ⁇ sterone, levonorgestrel and nomegestrol acetate
• progesterone preferably used as estrogenic component 17 ⁇ -estrad ⁇ ol (Es) and as progestogen component norethisterone acetate (NETA)
• Es estrogenic component 17 ⁇ -estrad ⁇ ol
• NETA progestogen component norethisterone acetate
• the transdermal matrix system according to l the invention may in particular simultaneously contain an estrogenic component and a progestational component.
• antioxidant agents commonly used by those skilled in the art, for example the products marketed by the company CIBA. - GEIGY under the name IRGANOX ⁇ such riRGANOX ® 565
• propyleneglycol laurate is meant HERE an ester of launic acid and propyleneglycol, that is to say a monoester, a diester or a mixture of propylene glycol mono- and diester (CH 3 -CHOH-CH 2 - OH) and launque acid (C ⁇ 2 H 24 O 2) will be particularly preferred a mixture of mono- and diester such as the product sold under the name Lauroglycol ® by the company Gattefosse
• N-alkyl-2-pyrrol ⁇ dones wherein the alkyl group is C 4 -C ⁇ s used in the present invention we prefer N-octyl-2-pyrrol ⁇ done marketed by the company GAF CORPORATION under the name SURFADONE ® LP 100
• the support receiving the matrix may be any support generally used in occlusive or non-occlusive transdermal systems, of variable thickness and impermeable to the constituents of the matrix
• a support in the form of polyethylene, polypropylene, polyester film, a complex (or composite) consisting of polyethylene and a copolymer of vinyl acetate and ethylene, or also foams
• an additional adhesive strip for example peripheral, could be added to the device to optimize its adhesion properties to the skin.
• This adhesive strip which describes a halo around the matrix system is formed of a pressure-sensitive adhesive well known to those skilled in the art.
• the surface of the matrix which is not bonded to the support may be covered with a peelable protective layer or film before using the Ledit device the device can itself be packaged in a waterproof protection such as, for example, polyethylene-aluminum complexes. Thanks to the specificity of the composition of the formulations which can form the matrix, only the matrix system according to the invention has the numerous advantages which we will now describe
• composition defined above containing (1) the pair (i) propylene glycol laurate and (n) a compound chosen from N-alkyl-2-pyrrolydones in which the alkyl group is C4- C15, (2) an SIS material, and (3) a VA / VP copolymer makes it possible to obtain a matrix delivery system for one and in particular several hormones, which has the desired ergonomic and therapeutic properties and makes it possible to obtain remarkable yields
• a particular synergistic effect between the nature of the poly (styrene- ⁇ soprene-styrene) copolymers which tend to "repel" the hormone (s) present which are hardly soluble in the latter
• (M) the specific role of plasticizer in propylene glycol laurate which will separate the polymer chains from SIS, allowing them greater movement and thus reducing the rigidity of the macromolecular network which in total facilitates the circulation of the hormone (s)
• this plasticizing compound which is a derivative of fatty substances, can, used in too large quantity, alter the adhesive and / or cohesive properties of the matrix. Also, it is essential that it is associated with a promoter of cutaneous permeation of a natural nature. different such as an N-alkyl-2-pyrrol ⁇ done to obtain the desired administration rates and achieve a better yield without significant loss of adhesion or cohesion
• the use of the VA / VP copolymer makes it possible to improve the solubility of the hormones that I use within the matrix
• this VA / VP copolymer is used in the adhesive masses because it improves the adhesion of the matrix and therefore the contact with the skin, it also causes a significant reduction in skin irritation which may be due to a mechanical effect of the system or to the combined effect of all of the compounds or to the effect of a particular compound such as a promoter r of skin permeation
• Transdermal matrix systems according to the invention are carried out according to the techniques generally used by those skilled in the art either by coating (in solvent phase), or according to the technique known as "hot-melt" (that is to say in the absence In both cases, in the context of industrial production, large surfaces are coated which are then cut out to give devices with suitable dimensions, depending on the quantity of hormone (s) present by area unit, at the selected dose of active ingredient to be administered for a determined time
• a thermostated reactor containing a solvent for the SIS polymer is introduced by heating to a temperature below the solvent boiling point (for example 50 to 60 ° C C in the case of the ethyl acetate) or the active ingredients, the VA / VP copolymer, the stabilizer, the N-alkyl-2-pyrrol ⁇ done and the propyleneglycol laurate and the mixture is stirred until the mixture is homogenized,
• step (2) the tackifying resin and the SIS copolymer are incorporated into the mixture obtained in step (1), still with stirring, while heating to the same temperature, and the components are homogenized until the constituents are completely dissolved;
• step (3) the homogeneous mixture thus obtained in step (2) is coated, at room temperature, on a temporary non-adherent support, for example a silicone polyester film at the rate of 50 to 300 g / m 2 , (4) the coating is heated to evaporate the solvent at a temperature, depending on the boiling point of the latter, between 40 and 110 ° C, and preferably a temperature of 60 to 80 ° C; and,
• a temporary non-adherent support for example a silicone polyester film at the rate of 50 to 300 g / m 2
• the coating is heated to evaporate the solvent at a temperature, depending on the boiling point of the latter, between 40 and 110 ° C, and preferably a temperature of 60 to 80 ° C; and,
• the tackifying resin is incorporated into the SIS polymer / stabilizer assembly, with stirring, at a temperature above 110 ° C., preferably a temperature of 180 ° C., in successive portions of 10%, 30% and 60%, so that each portion results in a perfectly homogeneous mixture;
• step (1a) then gradually incorporates into the mixture obtained in step (1a) propylene glycol laurate, N-alkyl-2-pyrrolidone, and the VA / VP copolymer always with stirring and at temperatures generally lower than step (1 a) determined by the thermal stability of these products; the mixture is again stirred until complete homogenization of the resulting mixture;
• step (2a) incorporating the active ingredient (s) into the homogeneous mixture thus obtained in step (2a), at a temperature of the order of 100 ° C., and stirring is continued until a perfectly homogeneous mixture is obtained;
• step (4a) the homogeneous mixture thus obtained is coated, at a temperature between 80 and 130 ° C, on a temporary non-adherent support, in particular a silicone polyester film, to obtain a deposit of 50 to 300 g / m 2 ; and, (5a) the matrix thus obtained in step (4a) is transferred to the chosen final support.
• a temporary non-adherent support in particular a silicone polyester film
• transdermal systems according to the invention are in particular useful for the treatment of the symptoms of menopause and of the cardiovascular risks which result therefrom, osteoporosis as well as for any therapy using the percutaneous route requiring the administration of estrogens and / or progestins. Best fashion
• the best embodiment of the invention consists in using a transdermal matrix system, the matrix of which contains for a total of 100 parts by weight (a) 34.3 parts by weight of SIS,
• the SIS used advantageously has a styrene content of between 14 and 50% by weight relative to the weight of said poly (SIS).
• the VA / VP copolymer advantageously has a vinyl acetate content of between 30 and 70% by weight relative to the weight of said VA / VP
• 0.25 g of 17 ⁇ -estrad ⁇ ol, 1 g of NETA, 3 g of PVP / VA-S-630 (copolymer of vinyl acetate and N-vinyl-2-pyrrolide) are successively introduced into a 250 ml beaker having a content of 40% by weight vinyl acetate units and marketed by GAF cORPORATION), 0, 1 g of IRGANOX ® 565 (an antioxidant marketed by CIBA-GEIGY), 2 g Surfadone LP 100 ® ( N-octyl-2- pyrrolidone marketed by the company GAF CORPORATION), 6 g of LAUROGLYCOL ® (mixture of propylene glycol mono- and diester and launque acid marketed by the company GATTEFOSSE) and 30 g of ethyl acetate
• the mixture obtained is coated on a silicone polyester film at a rate of (100 ⁇ 10) g / m 2 at room temperature (15-25 ° C).
• the coating thus produced is heated at 50 ° C for at least 30 minutes in order to evaporate the solvent and then transfer to a final support made of non-silicone polyester
• Example 4 The procedure is analogous to Example 1, but 0.25 g of 17 ⁇ -estrad ⁇ ol, 1.5 g of NETA, 1.5 g of PVP / VA-S-630, 0.1 g are used in this case.
• Example 4 The procedure is analogous to Example 1, but in this case 0 25 g of 17 ⁇ -estrad ⁇ ol is used 1 g of NETA, 1.5 g PVP / VA-S-630, 0.1 g IRGANOX ® 565, 2 g SURFADONE * LP 100, 7.5 g LAUROGLYCOL ® , 30 g ethyl
• Example 6 The procedure is analogous to Example 4 with the difference that in the present case, the coating is applied at the rate of (75 + 10) g / m 2
• Example 6 The procedure is analogous to Example 4 with the difference that in the present case, the coating is applied at the rate of (75 + 10) g / m 2
• Example 6 The procedure is analogous to Example 4 with the difference that in the present case, the coating is applied at the rate of (75 + 10) g / m 2
• Example 6
• Example 7 On procedure is analogous to example 6 but using in this case 0.5 g of 17 ⁇ -oestrad ⁇ ol, 1 g of PVP / VA S-630, 0, 1 g of IRGANOX ® 565, 2 g Surfadone LP ® 100, 7.5 g of LAUROGLYCOL ® , 30 g of ethyl acetate, 21 g of ECR ® 385 and 17.9 g of VECTOR ® 441 1 D.
• Example 8 The procedure described in Example 1 is carried out. but without 17 ⁇ - estradiol is incorporated in this case 2 g of NETA, 3 g of PVP / VA S-630, 0.1 g of IRGANOX ® 565, 2 g Surfadone LP 100 ®, 5.25 g Lauroglycol ® , 30 g of ethyl acetate, 22 g of ECR ® 385 and 15.65 g of VECTOR ® 421 1 D (SIS copolymer marketed by DEXCO company).
• Example 9 The procedure described in Example 1 is carried out. but without 17 ⁇ - estradiol is incorporated in this case 2 g of NETA, 3 g of PVP / VA S-630, 0.1 g of IRGANOX ® 565, 2 g Surfadone LP 100 ®, 5.25 g Lauroglycol ® , 30 g of ethyl acetate, 22 g of ECR ® 385
• the measurement of the amounts of hormone (s) released by a transdermal device with an area of 2.54 cm 2 previously cut out with a cookie cutter and deposited on a disc of 3.14 cm 2 of abdominal skin male "nude" mouse is carried out using a static glass cell, thermostatically controlled at 37 ° C. and having a receptor compartment with a volume of 11.5 ml containing as receiving phase a mixture of physiological saline / PEG 400 (75 / 25, v / v) Samples are taken from the receptor compartments at 2, 4, 6, 8, 12, 16, 20 and 24 hours, which are assayed by liquid chromatography.
• each permeation test for a sample of transdermal device is carried out on a minimum number of 3 to 5 skin samples.
• HERE a result which is the average for each device, obtained from these tests
• the device In the case of the ESTRAGEST ® TTS product, the device consists of two adjoining tanks containing a total of 10 mg of 17 ⁇ -estrad ⁇ ol and 30 mg of NETA, each tank containing a mixture of 5 mg of 17 ⁇ -oestradiol and 15 mg of NETA. then the measurements of skin permeation according to the same protocol on only one of the two reservoirs placed on a 3.14 cm 2 skin sample
• ex-vivo comparative measurements were also carried out on another skin model, the pig's ear skin, still in relation to said ESTRAGEST ® TTS.
• the operating protocol for these measurements is identical to that of the ex measurements.
• -vivo on abdominal skin of "nude" mice This time we have a 3.14 cm 2 disc of pig ear skin
• the receiving phase is in this case a physiological saline / PEG 400 / ethanol (66/18 / 16, v / v / v)
• samples were taken here for 48 hours.
• the result obtained is always the average obtained for each device tested on a minimum number of 3 to 5 skin samples
• Table III presents the results of the ex-vivo skin permeation tests on human skin of the devices of Examples 3 and 5 and of the product ESTRAGEST TTS
• Table IV shows the yields calculated for Examples 6 and 7 devices according to the invention and the product was finally OESCLIM ® compared the yields obtained for two devices
• Table IV shows, if we consider a system containing only 17 ⁇ -estrad ⁇ ol, that the systems according to the invention are also, from the point of view of yields, much higher than a product containing an estrogen alone, by example the product OESCLIM ® There is thus respectively, compared to OESCLIM ® 'a yield 8.2 times and 9.3 times higher for examples 6 and 7

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• 1995
  • 1995-09-27 FR FR9511325A patent/FR2739031B1/fr not_active Expired - Fee Related
• 1996
  • 1996-09-25 JP JP9513183A patent/JPH11514989A/ja active Pending
  • 1996-09-25 US US09/043,726 patent/US6007835A/en not_active Expired - Fee Related
  • 1996-09-25 CA CA002233171A patent/CA2233171A1/en not_active Abandoned
  • 1996-09-25 EP EP96932649A patent/EP0852493A1/de not_active Ceased
  • 1996-09-25 CN CN96197186A patent/CN1197389A/zh active Pending
  • 1996-09-25 WO PCT/FR1996/001496 patent/WO1997011689A1/fr not_active Application Discontinuation
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• 1998
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