GB2291593A - Nifepidine spray with ethyl oleate for enhancing absorption - Google Patents

Nifepidine spray with ethyl oleate for enhancing absorption Download PDF

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Publication number
GB2291593A
GB2291593A GB9515205A GB9515205A GB2291593A GB 2291593 A GB2291593 A GB 2291593A GB 9515205 A GB9515205 A GB 9515205A GB 9515205 A GB9515205 A GB 9515205A GB 2291593 A GB2291593 A GB 2291593A
Authority
GB
United Kingdom
Prior art keywords
mass
nifedipine
ethyl oleate
solution
parts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB9515205A
Other versions
GB2291593B (en
GB9515205D0 (en
Inventor
Margit Nagy
Csaba Farsang
Lodia Fedina
Katalin Szemeredi
Gabor Szenasi
Janos Egri
Antal Mosonyi
Borbala Baria
Gizella Toth
Ibolya Nyaradi
Frigyes Goergenyi
Zsuzsa Orr
Geza Floris
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.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of GB9515205D0 publication Critical patent/GB9515205D0/en
Publication of GB2291593A publication Critical patent/GB2291593A/en
Application granted granted Critical
Publication of GB2291593B publication Critical patent/GB2291593B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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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

Description

2291593 1 A PHARMACEUTICAL COMPOSITION FOR LOWERING THE BLOOD PRESSURE AND
A PROCESS FOR THE PREPARATION THEREOF 2_ 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, 10 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-(2nitrophenyl)-2,6-dimethyl-3,5-dimethoxycarbonyl1,4-dihydropyridine known under the international non-proprietory name of nifedipine, thus, it is widely employed 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 requirdments are sooner met by liquid pharmaceutical compositions, especially 30.-the sprayable solutions.
k i 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 10 % by mass of a dihydropyridine derivative e.g. nifedipine, 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.
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 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 that the polyvinylpyrrolidone easily forms a solid film, thus, 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 nifedipine 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 emergency conditions.
The aim of the invention is to provide a solution that 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.
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.
It is surprising that the hypotensive action of nifedipine 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 anesthesized by the ip. administration of go mg/kg of chloralose and 600 mglkg of urethane, then they were 30.-tracheotomized and a catheter was introduced into the left t h !5- -- femoral artery of each rat. The blood pressure was determined and continuously recorded by a tonometer type Statham P 23Gb. 30 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 contained 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 transferred to the oral mucosa contained 3 mg of nifedipine and 2.5 % by mass of ethyl oleate (the figure referring to the mass of the solution 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).
cl, 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 5 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.
A Table
Reduction of blood pressure in mm Hg 20 30 40 so 60 minutes after the treatment Sample examined 3 mg of nifedipine -27 3% of ethyl oleate - 4 3 mg of nifedipine + 2.5% of ethyl oleate -38 3 mg of nifedipine + 3% of ethyl oleate -44 3 mg of nifedipine + 3.5% of ethyl oleate 40 - 5 4 0 f -48 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 70 % by mass of ethanol, 10 to 30 % by mass of propylene glycol 10 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 30 is performed in a mechanical way by means of a pump, 19 consequently, the environment is not loaded by any propellant. The invention is further elucidated by means of the following Examples. Example 1 5 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 OC under stirring, then 3 parts bymass of ethyl oleate and 65.8 parts by mass of ethyl alcohol are added, and stirring is continued at 75 0 C. The homogeneous solution is cooled to 35-40 0 C, 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, a mechanical sprayer (i.e. pump) is placed into each container that is sealed and equipped with a spraying nozzle. Example 2 5 parts by mass of nifedipine are dissolved in a"mixture of 10 parts by mass of poly(ethylene glycol) (molecular weight: 20 400) and 64.5 parts by mass of ethyl alcohol at 55-60 0 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 0 C and 0.1 parts by mas S 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 0 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.
4 a 1 same temperature. To the solution obtained 2.5 parts by mass of ethyl oleate are admixed, the mixture is cooled to 35 OC and 0.1 parts by mass of a flavouring agent are added. Then the procedure of Example 1 is followed.
1 10 1 1 lo

Claims (2)

CLAIMS:
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 additive(s), characterized by containing also 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 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), characterized by is admixing 2 to 4 % by mass of ethyl oleate to the nifedipine solution during the preparation thereof.
0 A
GB9515205A 1994-07-26 1995-07-25 A pharmacuetical composition for lowering the blood pressure and a process for the preparation thereof Expired - Fee Related GB2291593B (en)

Applications Claiming Priority (1)

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

Publications (3)

Publication Number Publication Date
GB9515205D0 GB9515205D0 (en) 1995-09-20
GB2291593A true GB2291593A (en) 1996-01-31
GB2291593B GB2291593B (en) 1998-03-11

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ID=10985460

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GB9515205A Expired - Fee Related GB2291593B (en) 1994-07-26 1995-07-25 A pharmacuetical composition for lowering the blood pressure and a process for the preparation thereof

Country Status (18)

Country Link
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)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1848270A2 (en) * 2005-02-17 2007-10-31 Velcera Pharmaceuticals Transmucosal administration of drug compositions for treating and preventing disorders in animals
WO2008035020A3 (en) * 2006-09-22 2009-02-12 Philippe Perovitch Galenic form for the trans-mucosal delivery of active ingredients
EP2042161A1 (en) * 1997-10-01 2009-04-01 Novadel Pharma Inc. Propellant-free spray composition comprising anti-emetic agent
US20120027879A1 (en) * 1997-10-01 2012-02-02 Velcera, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7632517B2 (en) 1997-10-01 2009-12-15 Novadel Pharma Inc. Buccal, polar and non-polar spray containing zolpidem
DE102006027794A1 (en) * 2006-06-16 2007-12-20 Lts Lohmann Therapie-Systeme Ag Antihypertensive combination wafer

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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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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.
EP0267617B1 (en) * 1986-11-14 1992-06-24 Theratech, Inc. Penetration enhancement with binary system of cell envelope disordering compounds and lower alcohols
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

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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

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2042161A1 (en) * 1997-10-01 2009-04-01 Novadel Pharma Inc. Propellant-free spray composition comprising anti-emetic agent
US20120027879A1 (en) * 1997-10-01 2012-02-02 Velcera, Inc. Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders
EP1848270A2 (en) * 2005-02-17 2007-10-31 Velcera Pharmaceuticals Transmucosal administration of drug compositions for treating and preventing disorders in animals
EP1848270A4 (en) * 2005-02-17 2012-07-25 Velcera Pharmaceuticals Transmucosal administration of drug compositions for treating and preventing disorders in animals
EP2767163A1 (en) * 2005-02-17 2014-08-20 Abbott Laboratories Transmucosal administration of drug compositions for treating and preventing disorders in animals
US8940271B2 (en) 2005-02-17 2015-01-27 Abbott Laboratories Transmucosal administration of drug compositions for treating and preventing disorders in animals
WO2008035020A3 (en) * 2006-09-22 2009-02-12 Philippe Perovitch Galenic form for the trans-mucosal delivery of active ingredients
AU2007298814B2 (en) * 2006-09-22 2013-10-24 Marc Maury Galenic form for the trans-mucosal delivery of active ingredients

Also Published As

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EE9500029A (en) 1996-02-15
ITMI951621A1 (en) 1997-01-26
SK92295A3 (en) 1996-05-08
IT1277348B1 (en) 1997-11-10
FR2722988A1 (en) 1996-02-02
SK280463B6 (en) 2000-02-14
JPH08169829A (en) 1996-07-02
LV11026A (en) 1996-02-20
GB2291593B (en) 1998-03-11
UA39880C2 (en) 2001-07-16
YU50795A (en) 1998-05-15
AT402690B (en) 1997-07-25
CZ286399B6 (en) 2000-04-12
CZ181195A3 (en) 1996-02-14
PL309757A1 (en) 1996-02-05
ATA121495A (en) 1996-12-15
BE1011413A4 (en) 1999-09-07
LV11026B (en) 1996-04-20
HUT75457A (en) 1997-05-28
AU2326995A (en) 1996-02-08
LT4042B (en) 1996-09-25
HRP950374A2 (en) 1997-10-31
HU9402193D0 (en) 1994-09-28
AU699386B2 (en) 1998-12-03
PL181069B1 (en) 2001-05-31
DE19527140A1 (en) 1996-02-01
GB9515205D0 (en) 1995-09-20
FR2722988B1 (en) 1999-10-08
LT95084A (en) 1996-06-25
HU214582B (en) 1998-04-28
ITMI951621A0 (en) 1995-07-26

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 20020725