AU699386B2 - A pharmaceutical composition for lowering the blood pressure and a process for the preparation thereof - Google Patents

A pharmaceutical composition for lowering the blood pressure and a process for the preparation thereof Download PDF

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Publication number
AU699386B2
AU699386B2 AU23269/95A AU2326995A AU699386B2 AU 699386 B2 AU699386 B2 AU 699386B2 AU 23269/95 A AU23269/95 A AU 23269/95A AU 2326995 A AU2326995 A AU 2326995A AU 699386 B2 AU699386 B2 AU 699386B2
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AU
Australia
Prior art keywords
mass
nifedipine
solution
ethyl oleate
poly
Prior art date
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Ceased
Application number
AU23269/95A
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AU2326995A (en
Inventor
Borbala Barta
Janos Egri
Csaba Dr. Farsang
Lidia Fedina
Geza Floris
Frigyes Dr. Gorgenyi
Antal Mosonyi
Margit Dr. Nagy
Ibolya Nyaradi
Zsuzsa Orr
Katalin Dr. Szemeredi
Gabor Szenasi
Gizella Toth
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.)
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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Publication of AU2326995A publication Critical patent/AU2326995A/en
Application granted granted Critical
Publication of AU699386B2 publication Critical patent/AU699386B2/en
Anticipated expiration legal-status Critical
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Detergent Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

1
AUSTRALIA
Patents Act 1990
V~
Ii COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Actual Inventors: Address for Service: EGIS GY6GYSZERGYAR RT.
dr. Margit NAGY n~e Kriscfalussy dr. Csaba FARSANG Lidia FEDINA dr. Katalin SZEMER2DI G~bor SZENASI 36nos EGRI Antal MOSONYI Borb~la BARTA Gizella TOTH n6e Gyarmati Ibolya NYARADI dr. Frigyes GORGENYI Zsuzsa ORR G~za FLORIS CULLEN CO., Patent Trade Mark Attorneys, 240 Queen Street, Brisbane, Qld. 4000, Australia.
A PHARMACEUTICAL COMPOSITION FOR LOWERING THE BLOOD PRESSURE AND A PROCESS FOR THE PREPARATION THEREOF ft ftft I ft ft ''ft.
ft .tft C I I. ft C ft. ft ft ft Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us, 1 a i -la- The invention refers to a pharmaceutical composition and a process for the preparation thereof. Specifically, the invention refers to a sprayable nifedipine solution that comprises 1 to 5 by mass of nifedipine, 5 to 24 by mass of poly(ethylene glycol), 50 to 70 by mass of ethanol, to 30 by mass of propylene glycol and 0.1 to 0.5 by mass of additive(s) and a process for preparing the solution.
It is known that the blood circulation is effectively regulated by 4-(2-nitrophenyl)-2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine known under the international Snon-proprietory name of nifedipine, thus, it is widely employed S. 15 in various types of pharmaceutical compositions for the treatment of morbid conditions connected with the blood circulation.
The low solubility of nifedipine is a serious problem as to the absorption from solid pharmaceutical compositions as well as maintaining the nifedipine in a dissolved state in case of liquid pharmaceutical compositions. The above difficulties are often solved by adding huge quantities of surface active agents to the pharmaceutical compositions.
Recently, solid pharmaceutical compositions of nifedipine are available that produce either a relatively prolonged action, or a relatively quick action after administration. However, the treatment of anginal attacks or hypertonic emergency conditions requires a simple procedure of administration and, thereafter, an immediate action. In principle, these requirements are sooner met by liquid pharmaceutical compositions, especially the sprayable solutions.
A solution is described in DE-P 33 07 422 that can be administered either perorally in the form of drops, or in intravenous infusion. The known solution contains 0.5 to by mass of a dihydropyridine derivative e.g. nifedipine, 20 to 60 by mass of a solubility enhancing agent, preferably an ester of glyceryl-poly(ethylene glycol) and 80 to 40 by mass of a diluent consisting of water, ethanol, propylene glycol and/or poly(ethylene glycol). The drawback of the known composition resides in the rather high content of surface active agent that can lead to irritations of the oral mucosa in case .of peroral administration.
f 9 A sprayable solution is known from DE-P 35 44 692 wherein the dihydropyridine derivative such as nifedipine is dissolved in poly(ethylene glycol) and ethanol, optionally in the presence 15 of water and glycerol, and the solution contains 3 to 15 by mass of polyvinylpyrrolidone. According to the description, the active agent of the pharmaceutical composition has a quick action, however, it is a disadvantage of the known composition 9 *t that the polyvinylpyrrolidone easily forms a solid film, thus, 20 the spraying nozzle is often clogged due to drying of the polyvinylpyrrolidone. Even if the nozzle is not completely clogged, the amount of the sprayed nifedipine dosage becomes uncertain in the presence of polyvinylpyrrolidone since the sprayed dosage is lower than the required quantity until the solid polyvinylpyrrolidone separated in the nozzle is washed out by the solvent. Thus, if the known pharmaceutical composition is rarely used, the sprayed dosage will be always lower than the prescribed amount.
From EP 190 292 a pharmaceutical composition is known that can be transformed to an aerosol. The composition consists of -3nifedipine dissolved in a solvent containing poly(ethylene glycol) and/or glyceryl-poly(ethylene glycol)-oxystearate, and the solution is atomized by means of a propellant or a pump in a carrier gas stream. According to the examples of the description, the solvent consists of ethanol that may contain water and glycerol, too. A composition suitable for sublingual administration is also shown by certain examples.
In accordance with our examinations, the hypotensive action of the known pharmaceutical composition is not sufficient for the effective treatment of anginal attacks or hypertonic o. emergency conditions.
The aim of the invention is to provide a solution that S" can be sprayed by means of a pump, being suitable for sublingual administration and even a low dosage of it lowers the blood pressure in a short time.
S It was found that the above aim is fulfilled by a nifedipine solution containing, in addition to the conventional ingredients of nifedipine solutions, 2 to 4 by mass of ethyl oleate.
i n 4.
Ic is surprising tnat the nypotensive action oi nareaipin becomes significantly higher in the presence of 2 to 4 by mass of ethyl oleate, i.e. synergism is experienced between nifedipine and 2 to 4 by mass of ethyl oleate (the percentage of ethyl oleate refers to the mass of the whole composition).
The above synergism was shown by the following test: In the examinations, LATI and Charles River male rats were used that were hypertonic in a spontaneous manner. For each dose, 8 animals weighing 250 to 300 g each were employed. The animals were an(esthesized by the ip. administration of 90 mg/kg of chloralose and 600 mg/kg of urethane, then they were tracheotomized and a catheter was introduced into the left r
I
-4femoral artery of each rat. The blood pressure was determined and continuously recorded by a tonometer type Statham P 23Gb.
minutes after the surgical intervention a 10 minutes control period was left, then the sample to be examined was transferred to the oral mucosa of the animals, and the blood pressure was recorded for further 60 minutes.
The samples to be examined were as follows: Solution of Example 1. The dose transferred to the oral mucosa cnntained 3 mg of nifedipine and 3 by mass of ethyl oleate !the latter figure referring to the mass of the solution administered).
A solution similar to that of Example 1, however,.
comprising 2.5 by mass of ethyl oleate. The dose I transferred to the oral mucosa contained 3 mg of
S
I 15 nifedipine and 2.5 by mass of ethyl oleate (the latter figure referring to the mass of the solution a.
administered).
A solution similar to that of Example 1, however, comprising 3.5 by mass of ethyl oleate. The dose transferred to the oral mucosa contained 3 mg of nifedipine and 3.5 by mass of ethyl oleate (the latter figure referring to the mass of the solution administered).
A solution similar to that of Example 1, however, without any ethyl oleate. The dose transferred to the oral mucosa contained 3 mg of nifedipine.
A solution similar to that of Example 1, however, without any nifedipine. The dose transferred to the oral mucosa contained 3 by mass of ethyl oleate (the latter figure referring to the mass of the solution).
:13 D In case of deviation from the composition of Example 1, the amount of the solvents was increased or decreased according to the change of the quantity of ethyl oleate and the omission of nifedipine, respectively. In each case an amount of solution comprising 3 mg of nifedipine was administered to the animals.
(The same amount 0.103 g of the solution without any nifedipine was administered, too.) The reduction of blood pressure produced by the solutions examined are shown in the following Table. The blood pressures determined 10, 20, 30, 40, 50 and 60 minutes after the administration of the solution examined were compared to the blood pressure value determined before the administration of the solution to obtain the reductions given in the Table.
94*9 9 99 94 9 9 *4 *1 99 9 9) 44 *r 9 99r 9 9'4* 9.
99 9 .4.
Table Sample examined Reduction of blood pressure in mm Hg 10 20 30 40 50 minutes after the treatment 3 mg of nifedipine -27 3% of ethyl oleate 4 3 mg of nifedipine of ethyl oleate -38 3 mg of nifedipine 3% of ethyl oleate -44 3 mg of nifedipine of ethyl oleate -40 -29 5 -31 -30 -29 -28 4 4 4 3 -43 -42 -40 -41 -39 -44 -46 -47 -45 -42 -47 -49 -48 -47 1 -6- 0400 0 *1 00 0 S4 *i 4 00 0 00* 0 0* From the above data it can be seen that the hypotensive action of the composition of the invention is significantly higher than the sum of the hypotensive effect of the constituents when determined separately. Thus, there is a synergism between nifedipine and ethyl oleate.
The sprayable nifedipine solution of the invention is prepared by forming a solution from 1 to 5 by mass of nifedipine, 5 to 24 by mass of poly(ethylene glycol), 50 to by mass of ethanol, 10 to 30 by mass of propylene glycol and 0.1 to 0.5 by mass of additive(s) in a manner known per se, and admixing 2 to 4 by mass of ethyl oleate to the nifedipine solution during the preparation thereof.
In general, nifedipine is dissolved in a mixture of the organic solvents or a part thereof, and the remaining ingredients are added to the nifedipine solution obtained. The ethyl oleate is admixed to the organic solvent mixture comprising nifedipine, either before or after the addition of the remaining ingredients.
The one or more additive(s) can be a flavouring agent, a colouring agent etc.
The solution obtained is preferably filtered and filled into aerosol containers. A suitable pump is placed into each container, the latter is sealed and equipped with a spraying nozzle. Since nifedipine is rather sensitive to light, during the above operations the nifedipine solution should be protected from light.
The pharmaceutical composition of the invention is well absorbed sublingually and has a considerable effect in a very short time, thus, it is suitable for the effective treatment of anginal attacks or hypertonic emergency conditions. Spraying 0 is performed in a mechanical way by means of a pump, -I consequently, the environment is not loaded by any propellant.
The invention is further elucidated by means of the following Examples.
Example 1 2.9 parts by mass of nifedipine are added to a mixture of 10 parts by mass of poly(ethylene glycol) (molecular weight: 400) and 18.2 parts by mass of propylene glycol. The mixture obtained is heated to 75 °C under stirring, then 3 parts by mass of ethyl oleate and 65.8 parts by mass of ethyl alcohol are added, and stirring is continued at 75 The homogeneous solution is cooled to 35-40 0.1 parts by mass of a flavouring agent are added, stirred for further 5 minutes, then filtered through a glass filter having a pore size of G4 under nitrogen The filtrate is filled into aerosol containers of 20 g capacity, 9 S 15 a mechanical sprayer pump) is placed into each container that is sealed and equipped with a spraying nozzle.
Example 2 parts by mass of nifedipine are dissolved in a mixture of 10 parts by mass of poly(ethylene glycol) (molecular weight: 9 20 400) and 64.5 parts by mass of ethyl alcohol at 55-60 °C under stirring. To the solution obtained 16.9 parts by mass of propylene glycol and 3.5 parts by mass of ethyl oleate are admixed, the mixture is cooled to 35 C and 0.1 parts by mass of a flavouring agent are added under stirring, Then the procedure of Example 1 is followed.
Example 3 1 parts by mass of nifedipine is dissolved in 65.4 parts by mass of ethyl alcohol at 55-60 °C under stirring, then 12 parts by mass of poly(ethylene glycol) and 19 parts by mass -"of propylene glycol are added under constant stirring at the, sam-1 temperature. To the solution obtained 2.5 parts by mass of ethyl oleate are admixed, the mixture is cooled to 350 and 0.1 parts by mass of a flavouring agent are added. Then.
the procedure of Example 1 is followed.
*too

Claims (2)

1. A sprayable solution that comprises 1 to 5% by mass of nifedipine, 5 to 24% by mass of poly(ethylene glycol), 50 to 70% by mass of ethanol, 10 to 30% by mass of propylene glycol and 0.1 to 0.5% by mass of flavouring and/or colouring agent, characterised by also containing 2 to 4% by mass of ethyl oleate to enhance the hypotensive effect of nifedipine.
2. A process for preparing a sprayable nifedipine solution by forming a homogeneous solution comprising from 1 to 5% by mass of nifedipine, 5 to 24% by mass of poly(ethylene glycol), 50 to 70% by mass of o ethanol, 10 to 30% by mass of propylene glycol and 0.1 to 0.5% by mass of flavouring and/or colouring agent, characterized by admixing 2 to 4% by mass of ethyl oleate to the nifedipine solution during the preparation thereof. a DATED this 2 9 th day of September 1998 EGIS GY6GYSZERGYAR RT. By their Patent Attorneys CULLEN CO. *a S r- a /i^a Abstract A pharmaceutical composition for lowering the blood pressure and a process for the preparation thereof The invention refers to a sprayable nifedipine solution that comprises 1 to 5 by mass of nifedipine, 5 to 24 by m&as of poly(ethylene glycol), 50 to 70 by mass of ethanol, to 30 by mass of propylene glycol and 0.1 to 0.5 by mass S. of additive(s), said solution containing, in addition to.the above conventional ingredients of nifedipine solutions, 2 to 4 by mass of ethyl oleate. l* e 2
AU23269/95A 1994-07-26 1995-06-27 A pharmaceutical composition for lowering the blood pressure and a process for the preparation thereof Ceased AU699386B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9402193 1994-07-26
HU9402193A HU214582B (en) 1994-07-26 1994-07-26 Spayable antihypertensive composition and process for it`s production

Publications (2)

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AU2326995A AU2326995A (en) 1996-02-08
AU699386B2 true AU699386B2 (en) 1998-12-03

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AU23269/95A Ceased AU699386B2 (en) 1994-07-26 1995-06-27 A pharmaceutical composition for lowering the blood pressure and a process for the preparation thereof

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JP (1) JPH08169829A (en)
AT (1) AT402690B (en)
AU (1) AU699386B2 (en)
BE (1) BE1011413A4 (en)
CZ (1) CZ286399B6 (en)
DE (1) DE19527140A1 (en)
EE (1) EE9500029A (en)
FR (1) FR2722988B1 (en)
GB (1) GB2291593B (en)
HR (1) HRP950374A2 (en)
HU (1) HU214582B (en)
IT (1) IT1277348B1 (en)
LT (1) LT4042B (en)
LV (1) LV11026B (en)
PL (1) PL181069B1 (en)
SK (1) SK280463B6 (en)
UA (1) UA39880C2 (en)
YU (1) YU50795A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030095925A1 (en) * 1997-10-01 2003-05-22 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders
EP2042161A1 (en) * 1997-10-01 2009-04-01 Novadel Pharma Inc. Propellant-free spray composition comprising anti-emetic agent
US7632517B2 (en) 1997-10-01 2009-12-15 Novadel Pharma Inc. Buccal, polar and non-polar spray containing zolpidem
US8097614B2 (en) * 2005-02-17 2012-01-17 Velcera Pharmaceuticals, Inc. Transmucosal administration of meloxicam compositions for treating and preventing disorders in non-human domesticated animals
DE102006027794A1 (en) * 2006-06-16 2007-12-20 Lts Lohmann Therapie-Systeme Ag Antihypertensive combination wafer
FR2906140B1 (en) * 2006-09-22 2008-12-05 Philippe Perovitch GALENIC FORM FOR TRANSMUCOSUS ADMINISTRATION OF ACTIVE INGREDIENTS

Citations (2)

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Publication number Priority date Publication date Assignee Title
US4863970A (en) * 1986-11-14 1989-09-05 Theratech, Inc. Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols
US5298258A (en) * 1989-12-28 1994-03-29 Nitto Denko Corporation Acrylic oily gel bioadhesive material and acrylic oily gel preparation

Family Cites Families (10)

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Publication number Priority date Publication date Assignee Title
DE3307422A1 (en) * 1983-03-03 1984-09-06 Bayer Ag, 5090 Leverkusen LIQUID PREPARATIONS OF DIHYDROPYRIDINES, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST DISEASES
EP0175671A1 (en) 1984-08-23 1986-03-26 Kuhlemann & Co. Pharmaceutical preparation and method for the administration of this pharmaceutical preparation
DE3544692A1 (en) * 1985-12-18 1987-06-19 Bayer Ag DIHYDROPYRIDINE SPRAY, METHOD FOR THE PRODUCTION THEREOF AND ITS PHARMACEUTICAL USE
ES2038696T3 (en) * 1986-03-10 1996-07-16 Burghart Kurt PROCEDURE FOR PRODUCING A PHARMACEUTICAL PREPARATION.
DE3779999T2 (en) * 1986-11-14 1992-12-10 Theratech Inc INCREASE IN PENETRATION CAPABILITY BY MEANS OF A SUBSTANCE AND SHORT-CHAIN ALCOHOLIC SYSTEM CONTAINING CHANGES IN THE CELL HELL.
JPS63170316A (en) * 1986-12-30 1988-07-14 Fujimoto Seiyaku Kk Percutaneously absorbable pharmaceutical of nifedipine for external use
DE3714402A1 (en) * 1987-04-30 1988-11-10 Kali Chemie Pharma Gmbh DRUG FORMULATION
GB8828477D0 (en) * 1988-12-06 1989-01-05 Riker Laboratories Inc Medical aerosol formulations
AT391269B (en) * 1988-12-30 1990-09-10 Burghart Kurt PHARMACEUTICAL PREPARATION
HU205249B (en) * 1990-11-09 1992-04-28 Egyt Gyogyszervegyeszeti Gyar Process for producing suspensive aerosole composition

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4863970A (en) * 1986-11-14 1989-09-05 Theratech, Inc. Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols
US5298258A (en) * 1989-12-28 1994-03-29 Nitto Denko Corporation Acrylic oily gel bioadhesive material and acrylic oily gel preparation

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ITMI951621A1 (en) 1997-01-26
AT402690B (en) 1997-07-25
SK280463B6 (en) 2000-02-14
AU2326995A (en) 1996-02-08
HUT75457A (en) 1997-05-28
JPH08169829A (en) 1996-07-02
GB2291593B (en) 1998-03-11
BE1011413A4 (en) 1999-09-07
YU50795A (en) 1998-05-15
ATA121495A (en) 1996-12-15
FR2722988B1 (en) 1999-10-08
DE19527140A1 (en) 1996-02-01
SK92295A3 (en) 1996-05-08
HU214582B (en) 1998-04-28
GB2291593A (en) 1996-01-31
HRP950374A2 (en) 1997-10-31
ITMI951621A0 (en) 1995-07-26
PL309757A1 (en) 1996-02-05
LT95084A (en) 1996-06-25
HU9402193D0 (en) 1994-09-28
LT4042B (en) 1996-09-25
CZ286399B6 (en) 2000-04-12
CZ181195A3 (en) 1996-02-14
PL181069B1 (en) 2001-05-31
UA39880C2 (en) 2001-07-16
LV11026A (en) 1996-02-20
GB9515205D0 (en) 1995-09-20
LV11026B (en) 1996-04-20
IT1277348B1 (en) 1997-11-10
EE9500029A (en) 1996-02-15
FR2722988A1 (en) 1996-02-02

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