Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-05-17
2002-10-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C424S443000, C424S484000
Reexamination Certificate
active
06465005
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to devices for transdermal drug delivery and methods of making them. More particularly, this invention relates to the inhibition of the formation of crystals in a transdermal device such as a monolithic matrix transdermal system that delivers a hormone at therapeutically effective rates.
BACKGROUND OF THE INVENTION AND PRIOR ART STATEMENT
The transdermal route of parenteral delivery of drugs provides many advantages over other administration routes, such as slow controlled release and the avoidance of hepatic first-pass metabolism, (Stevenson et al. The Lancet, vol. 336, (1990) pp. 265). Several patent publications describe transdermal delivery devices for estradiol that are suitable for the treatment of gynaecological disorders such as climacteric disturbances and menstrual abnormalities.
For instance, U.S. Pat. No. 5518734 discloses a device for the transdermal administration of estradiol or estradiol and norethindrone acetate which includes an inhibitor of the enzymatic degradation of estradiol to estrone in the skin.
EP-A-0328806 discloses a drug-containing adhesive device for transdermal delivery system for estrogens which is free of any discrete permeable, polymeric, diffusion-controlling membrane.
WO 90/06120 patent discloses transdermal delivery of estradiol using a solvent system comprising oleic acid, linear alcohol, lactate and either dipropylene glycol or N-methyl-2-pyrrolidone. This solvent system may be used to prepare an adhesive matrix transdermal device or a reservoir transdermal device.
U.S. Pat. No. 4814168 discloses a dermal composition suitable for use in the transdermal delivery of drugs, which composition permits a high loading of a medicament. The dermal composition comprises a drug, a multi-polymer comprising vinyl acetate and ethylene monomers, a natural or synthetic rubber and a tackifying agent. WO 89/07951 discloses a pressure-sensitive adhesive sheet material for delivering estradiol to skin comprising a pressure sensitive adhesive polymer, two or more skin permeation enhancing ingredients and estradiol.
U.S. Pat. No. 5352457 discloses a method of preparing a device for transdermal delivery in which part or all the active ingredient is present in a saturated or supersaturated solution.
Protection of the endometrium from the effects of unopposed estradiol can be achieved by sequential treatment with norethisterone for two weeks of each 28-day cycle. (Ettinger B. Obstetrics and Gynaecology vol. 72, No 5 (supplement) 1988 pp. 12S, 31S, Whitehead et al. The Lancet, vol. 335, 1990 pp.310). Thus, a transdermal estradiol
orethindrone combination patch is a very desirable item.
Several documents relate to transdermal estradiol
orethindrone monolithic systems. For instance U.S. Pat. No. 5,518,734 mentioned above discloses a monolithic device system for the administration of estradiol by the transdermal route and a process of manufacturing said device; it also discloses that the system is versatile enough to allow the incorporation of a progestin such as norethindrone acetate.
U.S. Pat. No. 5,023,084 discloses a multicompartment—transdermal drug delivery system for delivery of norethindrone and estradiol. The system comprises a backing layer, an adhesive layer in which an estrogen is dissolved or microdispersed and adhered to this layer, an adhesive layer in which a progestin is also dissolved or microdispersed.
In monolithic transdermal systems, the hormone is dissolved in a pressure sensitive adhesive matrix. To deliver the desired therapeutic dose into the body, a supersaturated drug concentration is often needed. However, in such condition the system is thermodynamically unstable and the supersaturated drug has a tendency to precipitate or crystallize (Ma et al, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995)). Therefore, control of drug crystallization is of particular interest for transdermal systems; for example, Campbell et al. resorted in the method of heating to a temperature above the melting point of a crystalline hydrate to prevent the crystallization. (U.S. Pat. No. 4,832,953)
Ma et al (Int. J. of Pharm. 142 (1996) pp. 115-119) found that PVP added to the matrix act as an effective crystallization inhibitor for norethindrone acetate transdermal delivery systems.
Also, DE-A-4210711 affirms that cholesterol and SiO
2
are crystallization inhibitors for 17-&bgr;-estradiol transdermal delivery system.
Another document that describes a crystal inhibitor is WO 95/18603 which affirms that soluble PVP increases the solubility of a drug without negatively affecting the adhesivity or the rate of drug delivery from the pressure-sensitive adhesive composition.
Extensive development efforts have been devoted to design the process and equipment for the manufacture of a 7-day transdermal delivery patch which comply with the required delivery therapeutic daily rates of 17-&bgr;-estradiol and norethindrone acetate and also demonstrate satisfactory long term chemical and physical stability.
In the development of transdermal delivery systems, size is an important variable to consider. To deliver an adequate therapeutic dose having an adequate size, high concentrations of hormones are commonly needed.
Drug concentration in monolithic transdermal delivery systems can vary widely depending on the drug and polymer used. High concentrations of dissolved active ingredient can be used to increase flux of the active ingredient through the skin, as is shown in several patent publications.
Failure to control crystal size and distribution can result in products whose appearance suggests that the manufacturing process by which are produced are not under control. Also, the presence of crystals can result in loss of adhesion and could cause skin irritation.
In several coating matrixes we studied, crystallization in the adhesive depends on hormone concentration. As an example, we show in Table 1 the results obtained after manufacturing the transdermal units with different hormone concentration. Similar results have been obtained by Ma et al. (Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22 (1995) 712-713). The total drug concentration is important in affecting crystal growth. As the total drug concentration was increased, more crystal formation was observed.
TABLE 1
AMOUNT
CRYSTAL
CRYSTAL
CRYSTAL
(%)
OBSERVATION
OBSERVATION
OBSERVATION
OF HORMONES
Storage
Storage
Storage
IN THE
24 months
31 months
45 months
COATING MASS
ambient
ambient
ambient
LOT
MIXTURE
conditions
conditions
conditions
066
6
N.D.
N.D.
N.D.
066-B
9
+
++
++
067
12
++
+++
+++
N.D. = Not Detected
+ = Less than 10 crystals. In 16 square cm
++ = Between 10 and 20 crystals. In 16 square cm
+++ = More than 20 crystals. In 16 square cm
Matrix formulation: Acrylic adhesive, tackifier, oleic acid, propylene glycol, antioxidants, and hormones.
The hormones of this table are norethindrone acetate (NEA) and 17-&bgr;-estradiol (E2). Percent total hormones is NEA plus E2, and is given here as % by weight in the liquid solution before coating.
The manufacture of transdermal delivery patches containing less than 3% of active drug has been carried out for approximately seven years with no indication of the formation of any crystals, when the coating drying process was performed either in an infrared tunnel or in a hot air tunnel.
Usually the original laminate film dried in a conventional hot air tunnel exhibited no crystals or in some lots a low degree of crystallization. However when the laminate was fed through a die-cutting machine for the formation of the individual transdermal delivery patches, crystallization began around the edges of the cut with a “feather like” growth.
In the attempts to develop transdermal delivery patches that involve higher concentrations of the medicaments, we noticed that crystallization is different around the edges of the cut than in the centre or core of the patch. In the former, the crystals are us
Biali Fabián Isaac
Scasso Alejandro Fabio
Stefano Francisco Jose Evaristo
Amarin Technologies S.A.
Dann Dorfman Herrell and Skillman, P.C.
Ghali Isis
Page Thurman K.
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