Matrix adhering to nasal mucosa

Details Matrix adhering to nasal mucosa Matrix adhering to nasal mucosa

2002-02-21

2003-12-16

Venkat, Jyothsan (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S421000, C424S484000

Reexamination Certificate

active

06663883

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a matrix adhering to the nasal mucosa, which allows improved transfer, into the brain, of a drug exerting its effect in the brain and is capable of continuously supplying the drug into the brain.
BACKGROUND ART
As those literatures that disclose pharmaceutical compositions adsorbed into mucosae, the followings are known.
1) WO-A 98/42323 describes “A pharmaceutical composition comprising an unease inhibitor and an oil base material”, and there is an example of an agent adhering to mucosae on digestive tracts.
2) JP-A 5-132416 describes “A matrix adhering to mucosae on digestive tracts and being solid at ordinary temperature, wherein a material rendered viscous with water is dispersed in the vicinity of at least surface layers of matrix particles containing a polyglycerol fatty acid ester or lipid and an active ingredient”.
3) JP-A 10-324643 describes “A pharmaceutical composition adhering to mucosae on digestive tracts, which comprises a swelling agent for a material rendered viscous with water”.
On the other hand, as those literatures that disclose pharmaceutical compositions adhering to the nasal mucosa, the followings are known.
4) JP-A 56-100714 describes “A preparation adhering to mucosae on the oral or nasal cavity, wherein a drug layer comprising an ointment base material containing a drug and a surfactant is unevenly distributed in a mucosa-adhesive coating layer consisting of a cellulose ether and/or an acrylate polymer or a pharmaceutically acceptable salt thereof.”
5) JP-A 7-316038 describes “A pharmaceutical composition for administration into mucosae, which comprises a) an acrylic acid-alkyl (meth)acrylate copolymer or a salt thereof, b) an alkali metal salt and/or an alkaline earth metal salt, c) a drug and d) water as essential ingredients.”
6) JP-A 7-215843 discloses “A sustained release pharmacological composition adhering to biological tissues, which comprises a large number of micro-units containing at least one active ingredient and a means of regulating release of said active ingredient, wherein the micro-units do substantially not show biological adhesion before coating thereof, the respective micro-units are coated with a biologically adhering polymeric coating, the coating contains one or more physically acceptable polymers, at least one of the polymers is a biologically adhering polymer, and said coating endows the micro-units with an ability to adhere to biological tissues.”
7) U.S. Pat. No. 5,723,143 describes “A solid therapeutic or hygienic composition adhering to mucosae, which is used in administration into oral or nasal mucosae.”
8) WO-A 95/5163 describes “An emulsion adhering to the living body, which is useful as a pharmaceutical composition with enhanced transfer of a drug into mucosae on the living body.”
When a drug exerting its action on the brain is administered into the living body, transfer of the drug into the brain is significantly restricted by the blood-brain barrier. Accordingly, there is demand for a preparation capable of allowing a drug exerting its effect in the brain to exert the effect sufficiently in the brain.
DISCLOSURE OF THE INVENTION
The present inventors made extensive study for allowing a drug exerting its effect in the brain to exert the effect sufficiently in the brain, and as a result, they unexpectedly found for the first time that when a matrix comprising a polyglycerol fatty acid ester, said drug and a viscogenic substance was created, said matrix had excellent properties as a pharmaceutical preparation, for example excellent adhesion to the nasal mucosa, improved transfer of said drug into the brain, sustained supply of the drug into the brain, etc., and on the basis of this finding, this invention was completed.
That is, this invention relates to:
(1) a matrix adhering to the nasal mucosa which allows improved transfer into the brain of a drug exerting its effect in the brain, which comprises a polyglycerol fatty acid ester, the drug exerting its effect in the brain, and a viscogenic substance;
(2) the matrix according to the above-mentioned (1), wherein the polyglycerol fatty acid ester is an ester of a polyglycerol having a polymerization degree of 2 to 20 with a fatty acid having 12 to 22 carbon atoms;
(3) the matrix according to the above-mentioned (1), wherein the HLB of the polyglycerol fatty acid ester is 1 to 9;
(4) the matrix according to the above-mentioned (1), which comprises about 40 to about 95% by weight of the polyglycerol fatty acid ester;
(5) the matrix according to the above-mentioned (1), wherein the viscogenic substance is an acrylate type polymer or a salt thereof;
(6) the matrix according to the above-mentioned (5), wherein the molecular weight of the acrylate type polymer or a salt thereof is 1,000,000 to 6,000,000;
(7) the matrix according to the above-mentioned (1), which comprises about 4 to about 30% by weight of the viscogenic substance;
(8) the matrix according to the above-mentioned (1), which further comprises a swelling agent for the viscogenic substance;
(9) the matrix according to the above-mentioned (8), wherein the swelling agent for the viscogenic substance is curdlan and/or low-substituted hydroxypropylmethyl cellulose;
(10) the matrix according to the above-mentioned (1), which further comprises lipid;
(11) the matrix according to the above-mentioned (1), wherein the drug exerting its effect in the brain is a drug hardly transferring into the brain;
(12) the matrix according to the above-mentioned (1), wherein the drug exerting its effect in the brain is a sedative-hypnotic agent, an anti-anxiety agent, an antidepressant agent or an agent for treating Alzheimer's disease;
(13) the matrix according to the above-mentioned (1), wherein the drug exerting its effect in the brain is a compound having a melatonin receptor antagonist action;
(14) the matrix according to the above-mentioned (1),
wherein the drug exerting its effect in the brain is a compound represented by the formula:
wherein R
1
is a hydrocarbon group which may have a substituent group, an amino group which may have a substituent group or a heterocyclic group which may have a substituent group,
R
2
is a hydrogen atom or a hydrocarbon group which may have a substituent group,
R
3
is a hydrogen atom or a hydrocarbon group which may have a substituent group or a heterocyclic group which may have a substituent group,
X is CHR
4
, NR
4
, O or S whereupon R
4
represents a hydrogen atom or a hydrocarbon group which may have a substituent group,
Y is C, CH or N provided that when X represents CH
2
, Y is C or CH,
is a single or double bond,
ring A is a 5- to 7-memberred, oxygen atom-containing heterocyclic ring which may have a substituent group,
ring B is a benzene ring which may have a substituent group, and
m is an integer of 1 to 4; or a salt thereof;
(15) the matrix according to the above-mentioned (1), wherein the drug exerting its effect in the brain is (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl] propionamide;
(16) the matrix according to the above-mentioned (1), wherein the drug exerting its effect in the brain is (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl] acetamide;
(17) the matrix according to the above-mentioned (1), which comprises about 0.1 to about 50% by weight of the drug exerting its effect in the brain;
(18) a solid preparation comprising the matrix described in the above-mentioned (1);
(19) the solid preparation according to the above-mentioned (18), which is finely divided particles or powder;
(20) the solid preparation according to the above-mentioned (19), which is spherical;
(21) the solid preparation according to the above-mentioned (19), which has a particle diameter of about 0.1 to about 100 &mgr;m;
(22) a method of improving transfer, into the brain, of a drug exerting its effect in the brain, which comprises using a matrix comprising a polyglycerol fatty acid ester, said drug and a viscogenic substance; and
(23) use of a polyglycerol fatty acid ester,

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