Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
1999-03-01
2001-10-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C514S212010
Reexamination Certificate
active
06299888
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pharmaceutical preparations which contain azelastine hydrochloride as the pharmaceutically active ingredient but cause markedly little irritation to the skin.
PRIOR ART
Azelastine hydrochloride is widely being used as an anti-allergic agent mainly in the form of oral preparations in the treatment of diseases such as bronchial asthma, urticaria, and pruritus. In general the skin permeability of a basic drug is said to be high when the drug is in the undissociated form and low when the drug is in the dissociated form. Azelastine hydrochloride, as a basic drug, is thought to show better absorption at higher pHs at which the drug exists as undissociated molecules. However, because the dissociation constant (pKa) is as high as about 9.5, the pH of the pharmaceutical preparation needs to be about pH 9.5 so that the fraction of undissociated molecules may be 50% to ensure good skin permeability. However, such a pH is far higher than the physiological pH of the skin, mucosa, etc. That is, a pharmaceutical preparation having such a high pH is very irritative to the skin, possibly causing skin lesions. To lower the pH, an addition of a pH-adjusting agent may be an option, but at a low pH, most of the azelastine hydrochloride molecules exist in the dissociated form, so that addition of a large amount of such a pH-adjusting agent may decrease absorption. In addition, when the pH is below 4, the acidic conditions may cause skin lesions. Therefore addition of a pH-adjusting agent is not recommended.
Various investigations have been conducted on base ingredients that can enhance the absorption of azelastine hydrochloride within a physiologically acceptable pH range.
For example, the Japanese Unexamined Patent Publication No. Hei 2-124824 disclosed preparations containing monoglycerides of fatty acids having 8 to 12 carbon atoms and/or lactic acid esters of aliphatic alcohol having 12 to 18 carbon atoms, and the Japanese Unexamined Patent Publication No.Hei 6-40949 disclosed preparations containing fatty acids having 8 or more carbon atoms.
However, the additives used in the preparations disclosed in the above-mentioned publications are very irritative to the skin. Therefore there arises a new concern regarding the skin irritation of the additive itself, even though the percutaneous preparation combined with such an additive can solve the problem of skin lesions due to the high pH.
DISCLOSURE OF THE INVENTION
The present invention has been developed with such considerations in mind and its purpose is to provide an azelastine hydrochloride-containing preparation with low skin irritation and excellent percutaneous absorbability of azelastine hydrochloride, the pharmaceutically active ingredient.
In essence, an azelastine hydrochloride-containing percutaneous preparation of the present invention to be solved the above problems comprises {circle around (1)} hydrocarbons and/or beeswax, {circle around (2)} higher alcohols and/or polyhydric alcohols, and {circle around (3)} a surfactant.
BEST MODE FOR CARRYING OUT THE INVENTION
As described above, some methods have been disclosed to improve the skin permeability of azelastine hydrochloride without increasing the pH of the preparation, but these methods were unsatisfactory because they do not sufficiently consider the issue of reducing irritation to the skin. For example, the Japanese Unexamined Publication Patent Application No.Hei 6-40949 describes that “a fatty acid having 8 or more carbon atoms” added as an essential ingredient was selected as an additive with low irritation and high safety. However, some of the above fatty acids are high irritative to skin even when used alone according to an experiment by the present inventors. Thus it was found that the problem of the irritation of the preparations was not much solved and moreover the irritation persisted long after application.
Thus the skin irritation of azelastine hydrochloride-containing percutaneous pharmaceutical preparations had long been known, but had not been studied as the primary problem to be solved, and therefore the problem regarding the above skin irritation has not been solved to date. One of the main purpose in the present invention is to improve irritation to the skin, and another purpose of the present invention is to provide a preparation excellent in percutaneous absorbability of azelastine hydrochloride. For the above purposes, the present inventors have studied, as a result, they found that use of the above-mentioned base ingredients in the specified combination could achieve their purposes, and the present invention came about as a result of their research.
The fundamental concept of the present invention consists in the use of base ingredients prepared by appropriately combining only additives with low irritation, thereby to reduce not only the irritation due to the additives but also the irritation of the preparation as a whole, and at the same time to enhance the skin permeability of azelastine hydrochloride at a physiologically acceptable pH which will not cause skin lesions.
First the base ingredients which characterize the present invention are explained.
{circle around (1)} Hydrocarbons and/or Beeswax
These are frequently used as oily bases, being non-irritative and stable.
The hydrocarbons include saturated hydrocarbons represented by C
n
H
2n+2
[e.g. petrolatum (white petrolatum, yellow petrolatum, etc.), liquid paraffin, paraffin, etc.], materials containing a hydrocarbon as a major ingredient [e.g. gelatinized hydrocarbons prepared by dissolution of polyethylene resin in liquid paraffin by heating [Trade name “Plasty Base” (E. R. Squibb & Sons)], and waxes (microcrystalline wax, paraffin wax, etc.)]. Among them yellow petrolatum, white petrolatum, and gelatinized hydrocarbons are desirable.
Beeswax contains esters of higher fatty acids and higher monohydric alcohol as a major ingredient, including yellow beeswax and white beeswax, of which white beeswax is recommended.
These materials may be used alone or in combination of two or more.
The total content of the above-mentioned hydrocarbons and beeswax is preferable 10 to 97% of the whole amount of the preparation. When the content is below 10%, it is difficult for the preparation to maintain a semi-solid state; for example, creams may be separated into the solid phase and the aqueous phase, it is impossible to keep the preparation stable. The content is more preferable not less than 15%, and furthermore preferable not less than 20%. When the content is above 97%, it is impossible to add enough water to dissolve azelastine hydrochloride. As a result, their crystals is precipitated in the preparation, and the dispersion of the active ingredient is poor. The content is more preferable not be more than 95%, furthermore preferable not be more desirably not more than 90%.
{circle around (2)} Higher Alcohols and/or Polyhydric Alcohols
The above-mentioned higher alcohols are preferable saturated or unsaturated alcohols having 12 to 18 carbon atoms, such as aliphatic saturated alcohols [dodecanol (lauryl alcohol) (C=12), myristyl alcohol (C=14), cetanol (palmityl alcohol) (C=16), cetostearyl alcohol (mixture of cetanol and stearyl alcohol in equal amounts), stearyl alcohol (C=18), etc.], and aliphatic unsaturated alcohols [oleyl alcohol (C=18), etc.] and the like. Among these, cetanol, cetostearyl alcohol, and stearyl alcohol are recommended.
The above-mentioned polyhydric alcohols include those having 2 or more carbon atoms such as ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol, glycerol, sorbitol, etc. Among these, propylene glycol and polyethylene glycol are recommended.
These alcohols may be used alone or in combination of two or more.
The total content of the above-described higher alcohols and/or polyhydric alcohols is preferable 0.5 to 35% of the amount of the whole preparation. When the content is below 0.5%, the balance between the aqueous ph
Mizobuchi Noriko
Seto Sayuri
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
Pulliam Amy E
Teikoku Seiyaku Kabushiki Kaisha
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