AU700119B2 - Estradiol-TTS having water-binding additives - Google Patents

Estradiol-TTS having water-binding additives Download PDF

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Publication number
AU700119B2
AU700119B2 AU32583/95A AU3258395A AU700119B2 AU 700119 B2 AU700119 B2 AU 700119B2 AU 32583/95 A AU32583/95 A AU 32583/95A AU 3258395 A AU3258395 A AU 3258395A AU 700119 B2 AU700119 B2 AU 700119B2
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Australia
Prior art keywords
estradiol
water
transdermal therapeutic
therapeutic system
matrix
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AU32583/95A
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AU3258395A (en
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Hanshermann Franke
Michael Horstmann
Walter Muller
Thomas Pontzen
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LTS Lohmann Therapie Systeme AG
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LTS Lohmann Therapie Systeme AG
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30Oestrogens

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention concerns a transdermal therapeutic system which contains oestradiol as active substance and optionally further active substances as well as a hydrophylic additive. The therapeutic system has a layered structure comprising a backing which is impervious to the active substances and moisture, an active substance-containing matrix layer and, depending on the case, a separable protective layer. The system is characterized in that the hydrophylic additive is a component of the matrix.

Description

concentration, modification of the base polymer, and the like).
This finding, that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further in principle, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi, T. Higuchi: Physical Chemical Analysis of percutaneous process from creams and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1960).
The systems described in EP 0 421 454 comprise estradiol in an acrylate polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
With a lot of active substances, so-called "enhancers" may be added to the TTS during production. These are usually liquid admixtures improving the absorption properties of human skin; for this reason, they allow the absorption of the active substance from a sufficiently small TTS-surface. In particular readily volatile enhancers, ethanol used for the active substance estradiol, involve the problem of softening the TTS's adhesive layers to a great extent; above all they require additional bulky compartments in the system, rendering the TTS unacceptably thick. Finally, any additional non-polymeric additive involves the risk of incompatibility reactions on the skin, possibly even that of sensitization. The addition of certain less volatile, however, mostly less active enhancers glycerol esters, cyclic amides, eucalyptol) allows the production of matrix systems comprising the active substance and the absorption-promoting component in one or several monolithic layers.
US 4 863 738 represents one of many examples claiming the application of active substances, estradiol, together with a certain enhancer (in this case glycerol monooleate) in an optional TTS-matrix and in an optional concentration.
According to the art, these TTSs do not permit a satisfactory therapy either. The reason is that either the active enhancers are poorly tolerated by the skin or that the systems require unacceptably large surfaces owing to the still insufficient flow through the skin.
Another possibility of increasing the active substance flow through the skin is that an amount of active substance is dissolved molecularly disperse in the TTS, which exceeds that corresponding to the saturation solubility. With supersaturation of these systems the permeation rate of the skin increases to the same extent.
However, since such states are thermodynamically unstable, these forms of administration are not stable in storage; unforeseeable recrystallization of active substance particles will take place so that the flow rate through the skin gradually decreases to the saturation flow level; depending on the starting concentration, this results in losing a great portion of the initially existent therapeutic activity.
This process is a characteristic of estradiol.
At room temperature and normal relative air humidity (20-60% relative humidity), estradiol is not present in one of the two known anhydric modifications (I and II) but as a semihydrate (Busetti and Hospital, Acta Cryst. 1972, B28, 560). Owing to the layered structure stabilized via hydrogen bridges, and because of the diffusional compactness of the crystal compound, the semihydrate can be subjected to a short-term heat treatment to temperatures of about 170C without decomposition thereof (Kuhnert-Brandstutter and Winkler (1976) Scientia Pharmaceutica 44 177- 190). However, the anhydrous form can quantitatively be obtained already at about 120 0 C by way of enlarging the crystal surface by means of micronizing. According to own observations, the transformation already takes place at about 90 0 C if heating is conducted very slowly (0.2-1 K/min) and in case of a particularly finecrystalline substance.
With decreasing partial water vapor pressure, on the other hand, estradiol has a higher solubility in some polymers, particularly in polyacrylates. According to Fick's law, higher concentrations with otherwise same conditions increase the diffusion flow through the skin; for this reason such a concentration increase is very desirable in transdermal therapeutic systems. However, the water introduced with the estradiol-semihydrate is already sufficient to initiate gradual recrystallization from the solution as estradiol-semihydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia Pharmaceutica 44 177-190). After crystallization, the flow rate from the system to the skin considerably decreases with the diminishing concentration.
Taking into account these circumstances, transdermal therapeutic systems are known that offer a pharmacotherapeutically satisfying solution by exactly regulating the concentration to little less than the saturation solubility of the estradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved, disperse estradiol-anhydrate (DE-PS 42 23 360).
Even in consideration of this state of the art, it is important to maintain a sufficiently low atmospheric humidity during production and storage of an estradiol-TTS in order to avoid large-area precipitation of the poorly soluble estradiol-semihydrate. To this end, a waterproof package having a low water-vapor permeability can be used in principle. However, owing to the low estradiol concentration contained in today's TTSs, very small amounts of humidity are sufficient to cause precipitation of the estradiol-semihydrate.
If, for example, 2 mg of anEstradiol (anhydrous) are present in a TTS in dissolved form, an amount of only 66.1 pg of water can cause complete precipitation. Using conventional packaging means, it is therefore very difficult to exclude entry of such small quantities of moisture over storage periods of several years.
P:\WPDOCS\NEH\SPEC\3258395.SPE27/1 0/98 DE 42 37 453 already proposes to use desiccants in the ready-for-storage package; however, there are no indications with respect to using the water-binding additive as a component of the matrix.
Accordingly, it is the object of the present invention to provide a transdermal therapeutic system comprising estradiol, that protects the system in the package during storage against precipitation of the estradiol-semihydrate, and which, if required, is suitable for a matrix which comprises more active substance in a molecularly disperse dissolved form than corresponds to the saturation solubility.
In accordance with a first step of this invention there is provided a transdermal therapeutic system with the active substance estradiol and, optionally, further active substances having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix and, optionally, a removable protective layer characterized in that the matrix contains the active substance as anhydrous estradiol, together with a water-binding additive, said water-binding additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.
Integrating water-binding mineral components in the substance of the matrix according to the present invention can be realized in a TTS in different manners: the most simple form is a single-layer matrix system the matrix of which simultaneously has a pressure-sensitive adhesive function, rendering an additional adhesive layer superfluous.
The matrix may exhibit several active substance-containing layers, with at least one of these ayers comprising a pharmaceutically acceptable, water-binding mineral additive.
If a membrane which is hardly permeable to estradiol is introduced between such a matrix, which comprises estradiol and water-binding mineral constituents, and the adhesive layer, a modified active substance release is achieved.
In addition to the wide-spread acrylic-acid ester copolymers suitable for the use with estradiol, other polymers may also be used as base material, for example, polyisobutylene, polyvinyl acetate, and copolymers, synthetic rubber, silicones.
p:\WPDOCS\NEH\SPEC\3258395.SPE271 0/98 6 In any case, the characterizing feature of transdermal therapeutic systems according to the present invention is the presence of water-binding mineral components in the matrix. In this connection, the exact amount of said additives in the matrix must be sufficiently large since this increases the total moisture-binding capacity in the system. The exact amount of added substances will result for the artisan in a comprehensible manner from the component's binding power for water. Since the water-binding capacity of most of the following exemplary substances generally lies above that of estradiol, an addition in the range of estradiol contained about 1 to 2 percent may be considered as minimum amount. The upper limit is determined by mechanical values, such as flowability of the matrix, adhesive force, and processibility. In general, a proportion of 10 to 50 percent by weight, preferably between and 35 percent by weight is desired. Alternatively, the proportion of the mineral water-binding additive is the total matrix material may be between 1 to 40 percent by weight, and preferably percent by weight.
The following substances may be used as water-binding mineral components, eg, zinc oxide, silicon dioxide silica gel (also in modified, eg, hydrophobized form), talc, phosphorus pentaoxide, alumina, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and hydroxide, kaolin, molecular sieves, sodium oxide, calcium and magnesium carbonate, magnesium sulfate, calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates, or magnesium perchlorate.
In this connection, it must be considered that both chemico-reactive processes, such as the reaction of magnesium oxide to magnesium hydroxide, and the physical changes, eg, inclusion 9 of crystal water into initially anhydrous sodium sulfate, calcium sulfate, or calcium chloride, or also pure, nonstoichiometric hygroscopy or adsorptivity can be utilized; these are commonly known as such to the skilled artisan.
0 Substances having a high water-binding capacity in case of low humidity (in the range of below about 5 percent relative humidity) are preferably used. In addition, a high degree of physiological compatibility is desired.
Fortunately, many hydrates of salts of the alkaline earth metals and alkali metals comply with these conditions, for example, calcium and magnesium carbonate, calcium, sodium, and P:\WPDOCS\NEH\SPEC\3258395.SPE:27/1 0198 7 magnesium sulfate, or many silicates, aluminates, borates, and phosphates of the alkali metals (preferably sodium, potassium, lithium) and alkaline earth metals (calcium and magnesium).
The matrix base material may be a polymer which, under water-free conditions, has a solubility for the active estradiol of between 0.4 and 3.0 percent by weight.
In another aspect of this invention there is provided a process for the production of the transdermal therapeutic system according to one or several of the preceding claims, characterized by the steps: preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, using this suspension, applying a layer on a sheet-like substrate, carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the layer by heating to 90° to 1750C.
Preferably, the dry layer is heated to 90° to 2000C until a conversion of the hydrous form of the mineral water-binding additive into its anhydrous form has taken place.
0* The transdermal therapeutic system may be packed into a moisture proof package with comprises a desiccant.
Additional embodiments of the present invention are provided according to the subclaims.
0 Examples: .Example 1: Production of a system according to the present invention 2.0 g of 17-j-estradiol-semihydrate, micronized g of Cariflex® TR 1107 (styrene-isoprene-styrene block copolymer) 120.0 g of Staybelite Ester 5E (thermoplastic ester gum of colophony derivatives) g of viscous paraffin g of calcium sulfate dihydrate are molten in an evacuatable kneader at 130 0 C and brought into an externally homogeneous form by means of kneading within ten hours. Under vacuum (less than 0.02 bar) heating to 165 0 C is effected for one hour, while doing so crystal water is driven off the Sactive substance and calcium sulfate by means of kneading.
The melt is cooled down to 120C; in a continuous coating line it is subsequently coated onto a siliconized polyester film of 100 pm thickness in such a manner that the weight per unit area of the layer amounts to 200 g/m 2 Afterwards a polyester film 15 pm thick is applied (laminated) under roll pressure on the still hot layer, avoiding the formation of air bubbles.
Transdermal systems of 16 cm 2 are obtained by punching using a wad punch.
Example 2: Production of a system according to the present invention g of 17-P-estradiol-semihydrate, micronized 400.0 g of acrylic-acid ester copolymer solution (solids content w/w) 70.0 g of calcium sulfate, anhydrous ("anhydrite") are stirred at room temperature in a cylindrical glass vessel until a homogeneous suspension is obtained. Afterwards coating is effected at a slit width of 500 pm onto a 100 pm siliconized polyester film. The coating is dried at 25?C, at 50 0 C, at 80 0 C and at 95 0 C, each time-for 10 minutes. A 15 pm polyester film is immediately applied (laminated) on the dry layer under roller pressure, avoiding the formation of air bubbles.
Transdermal systems of 10 cm 2 are obtained by punching using a wad punch. These are packed into a composite packaging material of. paper/aluminum foil/hot-sealing layer under addition of a desiccant tablet comprising 0.3 g of calcium sulfate (previously predried atl 80 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of intergers but not the exclusion of any other integer or step or group of integers or steps.
a a a 4 a ••oo o **o P:\VVPDOCS\NEH\SPEC\3258395.SPE:27/1 0/98 The claims defining the invention are as follows: 1 A transdermal therapeutic system with the active substance estradiol and, optionally, further active substances having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix and, optionally, a removable protective layer characterized in that the matrix contains the active substance as anhydrous estradiol, together with a water-binding additive, said water-binding additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.
2 The transdermal therapeutic system according to claim 1 characterized int hat the matrix exhibits several active substance-containing layers and that at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.
3. The transdermal therapeutic system according to claim 1 or 2 characterized int hat the matrix material comprises the water-binding additive substance in finely dispersed S; suspension.
4. The transdermal therapeutic system according to claim 1 characterized int hat the water-binding additive substance is a mineral.
5. The transdermal therapeutic system according to any one of claims 1 to 4 S• characterized in that the water-binding additive is the anhydrate of an alkaline-earth or alkali metal salt.
6. The transdermal therapeutic system according to any one of claims 1 to 4 characterized in that the water-binding additive is the semihydrate or anhydrate ("anhydrite") of calcium sulfate.

Claims (7)

  1. 7. The transdermal therapeutic system according to one or several of claims 1 to 6 characterized in that the estradiol is present as dispersion of an anhydrous crystallizate.
  2. 8. The transdermal therapeutic system according to one or several of claims 1 to 7 characterized in that more estradiol is comprised in the matrix base material in molecularly disperse dissolved form than corresponds to the saturation solubility.
  3. 9. The transdermal therapeutic system according to one or several of claims 1 to 8 characterized in that the proportion of the mineral water-binding additive in the total matrix material amounts to be- tween 1 and 40%-wt., and preferably to The transdermal therapeutic system according to one or sev- eral of claims 1 to 9 characterized in that the matrix base material is a polymer which, under water-free conditions, has a solubility for the active substance estradiol of between 0.4 and
  4. 11. The transdermal therapeutic system according to claim characterized in that the matrix base material is a polyacrylate polymer.
  5. 12. A process for the production of the transdermal therapeutic system according to one or several of the preceding claims, char- acterized by the steps: preparing a suspension of estradiol-semihydrate and water-bind- ing mineral additive in a solution, dispersion, or melt of the matrix base material, using this suspension, applying a layer on a sheet-like substrate, carrying out a conversion of estradiol-semihydrate into anhy- drous estradiol in the layer by heating to 90 to 175 0 C. 12
  6. 13. The process according to claim 12 characterized in that the dry layer is heated to 90 to 200 0 C until a conversion of the hy- drous form of the mineral water-binding additive into its anhydrous form has taken place.
  7. 14. The process according to any one of claims 12 or 13 charac- terized in that the transdermal therapeutic system is packed into a moistureproof package which comprises a desiccant, if required. r 13 ABSTRACT A transdermal therapeutic system with the active substance es- tradiol and, optionally, additional active substances and with a water-binding additive, having a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, if necessary, a re- movable protective layer, is characterized by the fact that the water-binding additive is a component of the matrix.
AU32583/95A 1994-08-20 1995-08-12 Estradiol-TTS having water-binding additives Ceased AU700119B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4429664 1994-08-20
DE4429664A DE4429664C2 (en) 1994-08-20 1994-08-20 Estradiol TTS with water-binding additives and process for its preparation
PCT/EP1995/003202 WO1996005815A1 (en) 1994-08-20 1995-08-12 Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives

Publications (2)

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AU3258395A AU3258395A (en) 1996-03-14
AU700119B2 true AU700119B2 (en) 1998-12-24

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AU32583/95A Ceased AU700119B2 (en) 1994-08-20 1995-08-12 Estradiol-TTS having water-binding additives

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EP (1) EP0776197B1 (en)
JP (1) JPH10504314A (en)
KR (1) KR100374476B1 (en)
CN (1) CN1073413C (en)
AT (1) ATE173163T1 (en)
AU (1) AU700119B2 (en)
CA (1) CA2197865C (en)
CZ (1) CZ50897A3 (en)
DE (2) DE4429664C2 (en)
DK (1) DK0776197T3 (en)
ES (1) ES2126308T3 (en)
FI (1) FI118721B (en)
HU (1) HUT77093A (en)
IL (1) IL114948A (en)
NO (1) NO970553L (en)
NZ (1) NZ291449A (en)
PL (1) PL180943B1 (en)
SI (1) SI0776197T1 (en)
SK (1) SK280299B6 (en)
WO (1) WO1996005815A1 (en)
ZA (1) ZA956926B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6623763B2 (en) 1996-01-08 2003-09-23 Lts Lohmann Therape-System Ag Pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system for the release of 17-β-estradiol to the human organism
DE19600347A1 (en) * 1996-01-08 1997-07-10 Lohmann Therapie Syst Lts Skin-adhering pharmaceutical preparation, in particular TTS for the delivery of 17-beta-estradiol to the human organism
GB9720470D0 (en) 1997-09-25 1997-11-26 Ethical Pharmaceuticals South Inhibition of crystallization in transdermal devices
DE19827732A1 (en) * 1998-06-22 1999-12-23 Rottapharm Bv Transdermal patch useful for hormone replacement therapy used for treatment of menopausal symptoms

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6712090A (en) * 1989-10-13 1991-05-16 Watson Laboratories, Inc. Drug delivery systems and matrix therefor
DE4223360C1 (en) * 1992-07-16 1993-04-08 Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De
DE4237453C1 (en) * 1992-11-06 1993-08-19 Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De
DE4309830C1 (en) * 1993-03-26 1994-05-05 Lohmann Therapie Syst Lts Transdermal patches for oestradiol admin. - contg. isopropylidene mono- or di-glycerol as penetration enhancer

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SK280299B6 (en) 1999-11-08
CA2197865C (en) 2005-10-25
KR970705380A (en) 1997-10-09
SI0776197T1 (en) 1999-04-30
KR100374476B1 (en) 2003-04-23
MX9701301A (en) 1998-05-31
IL114948A (en) 2000-10-31
WO1996005815A1 (en) 1996-02-29
ES2126308T3 (en) 1999-03-16
IL114948A0 (en) 1995-12-08
CZ50897A3 (en) 1997-06-11
ATE173163T1 (en) 1998-11-15
PL180943B1 (en) 2001-05-31
AU3258395A (en) 1996-03-14
SK21997A3 (en) 1997-07-09
CN1155836A (en) 1997-07-30
DE59504233D1 (en) 1998-12-17
DK0776197T3 (en) 1999-07-26
DE4429664C2 (en) 1997-09-11
CN1073413C (en) 2001-10-24
EP0776197B1 (en) 1998-11-11
FI970702A (en) 1997-02-19
PL319014A1 (en) 1997-07-21
EP0776197A1 (en) 1997-06-04
HUT77093A (en) 1998-03-02
DE4429664A1 (en) 1996-02-22
ZA956926B (en) 1996-03-25
NO970553D0 (en) 1997-02-06
NO970553L (en) 1997-02-06
CA2197865A1 (en) 1996-02-29
FI118721B (en) 2008-02-29
NZ291449A (en) 1998-09-24
FI970702A0 (en) 1997-02-19
JPH10504314A (en) 1998-04-28

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