CA1245157A - Percutaneous administration type pharmaceutical preparation in tape form - Google Patents
Percutaneous administration type pharmaceutical preparation in tape formInfo
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- CA1245157A CA1245157A CA000466151A CA466151A CA1245157A CA 1245157 A CA1245157 A CA 1245157A CA 000466151 A CA000466151 A CA 000466151A CA 466151 A CA466151 A CA 466151A CA 1245157 A CA1245157 A CA 1245157A
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- acrylate
- adhesive base
- concentration
- base material
- mole
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Abstract
ABSTRACT OF THE DISCLOSURE
A percutaneous administration type pharmaceutical preparation in tape form is disclosed which comprises a flex-ible backing, which is non-permeable to the active ingredient, and an adhesive base layer formed on said flexible backing.
The adhesive base layer consists essentially of an adhesive base material and an active ingredient compatible with said adhesive base material. The adhesive base material is a copolymer containing 2-ethylhexyl acrylate (EHA) in a concen-tration of 45 mole% or more and N-vinyl-2-pyrrolidone (VP) in a concentration of 20 to 55 mole%, while the active ingredient is isosorbide dinitrate (ISDN) which is contained in the said adhesive base material in a concentration of 10% by weight or more.
A percutaneous administration type pharmaceutical preparation in tape form is disclosed which comprises a flex-ible backing, which is non-permeable to the active ingredient, and an adhesive base layer formed on said flexible backing.
The adhesive base layer consists essentially of an adhesive base material and an active ingredient compatible with said adhesive base material. The adhesive base material is a copolymer containing 2-ethylhexyl acrylate (EHA) in a concen-tration of 45 mole% or more and N-vinyl-2-pyrrolidone (VP) in a concentration of 20 to 55 mole%, while the active ingredient is isosorbide dinitrate (ISDN) which is contained in the said adhesive base material in a concentration of 10% by weight or more.
Description
lZ4~157 The present invention relates to a percutaneous administration type pharmaceutical preparation in tape form containing isosorbide dinitrate (ISDN) as an active ingredient therein.
Isosorbide dinitrate (ISDN) and nitroglycerin (NG) are known as effective medicines for angina pectoris. However, neither of these is effective over a prolonged period of application nor are they effective in suppressing or preventing attacks of angina pectoris after an initial period of effect-iveness. Therefore, a pharmaceutical preparation which would supply ISDN gradually and at a constant rate over a long period of time has been desired.
In an effort to overcome these deficiencies, a percutaneous absorption type pharamaceutical preparation in tape form containing ISDN or pentaerythritol tetranitrate (PETN) has been proposed in U.S. Patent No. 4,420,470 wherein the adhesive base material is composed of a copolymer contain-ing alkyl acrylate or methacrylate in a concentration of at least 50% by weight, a functional monomer in a concentration of up to 20% by weight and a vinyl ester monomer in a concentra-tion of up to 40~ by weight. However, such a percutaneous absorption type pharmaceutical preparation in tape form has the following three critical drawbacks:
Firstly, since such a pharmaceutical preparation is administered via the skin having a tissue which serves to prevent foreign substances from entering into the body, it is difficult to administer an amount of active ingredients which is sufficient to exert an immediate pharmaceutical effect.
Thus, a large-sized tape must be applied to the skin and/or an absorption promoter must be incorporated into the adhesive base material.
Secondly, this pharmaceutical preparation necessarily has a side effect. Due to contact of the adhesive base layer with the skin over a given period of time, the normal secretion, metabolism, expansion and construction of the skin are prevented and the skin suffers irritation at the edge portion of the tape and/or . . _ ~.
from the adhesive base layer thereof, resulting in a number of red spots, and in extreme cases, incrustations and/or edemata, on the skin,which can remain for several days.
Thirdly, a part of the adhesive base mater~al unavoidably remains on the skin when the tape i~ peeled off.
Additionally, a part of the active ingredients contained in the adhesive base material can penetrate through the backing, and/or crystalize at the lnterface of the adhesive base layer and the backing thereby resulting in reduced pharmaceutical effect.
This invention was completely based on a knowledge of the inventors that an adhesive base material allowing a quick supply of ISDN to the skin should be selected from adhesive materials in which ISDN can be dissolved; skin irritation can be reduced by using adhesive materials having excellent hydrophilic propertles; and, for reduction of skin irritation, adhesive materials containing polar monomers such as acrylic acid, methacrylic acid, etc., should not be employed for an adhesive base material, while adheqive materials containing a monomer, N-vinyl-2-pyrrolidone (VP), are desirable thereof.
Isosorbide dinitrate (ISDN) and nitroglycerin (NG) are known as effective medicines for angina pectoris. However, neither of these is effective over a prolonged period of application nor are they effective in suppressing or preventing attacks of angina pectoris after an initial period of effect-iveness. Therefore, a pharmaceutical preparation which would supply ISDN gradually and at a constant rate over a long period of time has been desired.
In an effort to overcome these deficiencies, a percutaneous absorption type pharamaceutical preparation in tape form containing ISDN or pentaerythritol tetranitrate (PETN) has been proposed in U.S. Patent No. 4,420,470 wherein the adhesive base material is composed of a copolymer contain-ing alkyl acrylate or methacrylate in a concentration of at least 50% by weight, a functional monomer in a concentration of up to 20% by weight and a vinyl ester monomer in a concentra-tion of up to 40~ by weight. However, such a percutaneous absorption type pharmaceutical preparation in tape form has the following three critical drawbacks:
Firstly, since such a pharmaceutical preparation is administered via the skin having a tissue which serves to prevent foreign substances from entering into the body, it is difficult to administer an amount of active ingredients which is sufficient to exert an immediate pharmaceutical effect.
Thus, a large-sized tape must be applied to the skin and/or an absorption promoter must be incorporated into the adhesive base material.
Secondly, this pharmaceutical preparation necessarily has a side effect. Due to contact of the adhesive base layer with the skin over a given period of time, the normal secretion, metabolism, expansion and construction of the skin are prevented and the skin suffers irritation at the edge portion of the tape and/or . . _ ~.
from the adhesive base layer thereof, resulting in a number of red spots, and in extreme cases, incrustations and/or edemata, on the skin,which can remain for several days.
Thirdly, a part of the adhesive base mater~al unavoidably remains on the skin when the tape i~ peeled off.
Additionally, a part of the active ingredients contained in the adhesive base material can penetrate through the backing, and/or crystalize at the lnterface of the adhesive base layer and the backing thereby resulting in reduced pharmaceutical effect.
This invention was completely based on a knowledge of the inventors that an adhesive base material allowing a quick supply of ISDN to the skin should be selected from adhesive materials in which ISDN can be dissolved; skin irritation can be reduced by using adhesive materials having excellent hydrophilic propertles; and, for reduction of skin irritation, adhesive materials containing polar monomers such as acrylic acid, methacrylic acid, etc., should not be employed for an adhesive base material, while adheqive materials containing a monomer, N-vinyl-2-pyrrolidone (VP), are desirable thereof.
2~ Accordingly, the invention provides a percutaneous admlnistration type pharmaceutical pr0paration in tape form comprising a flexlble backing, whic~ non-permeable to the active ingredient, and an adhesive base layer formed on said flexible backing; the adhesive base layer consisting essentially of an adhesive base material and an active ingredient compatible with said adhesive base material, wherein the adhesive base material is a copolymer containing 2-ethylhexyl acrylate (EHA) in a concentration of 45 to 80 mole %, a (meth)acrylate monomer in a concentration of 0 to 35 mole %, which comprises one or more members selected f rom the group consisting of propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acylate, octyl ,, lZ~S157 - 2a -acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate, and N-vinyl-2-pyrrolidone (VP) in a concentration of 20 to 55 mole %, wlth the sum of the mole % of EHA, (meth~acrylate and VP being 100, and with the EHA/VP ratio in mole % being in the range of from 80/20 to 45/55, and the active ingredient is isosorbide denitrate (ISDN) which is present in said adhesive base material in a concentration of 10 to 30% by weight and in a concentration of B0 to 100 iexclusive) % of the saturated solubility concentration of ISDN in said adhesive base material.
In a preferred embodiment, the adhesive ba~e material compri~es a copolymer containing EHA in a concentration of 55 mole~ or more and VP in a concentration of 30 to 45 1~45~57 mole%, and the concentration of ISDN in the adhesive base material is 13~ by weight or more.
The adhesive base material may also contain a (meth)-acrylate monomer, in a concentration of 35 mole~ or less, which comprises one or more monomers selected from the group consisting of propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate.
The adhesive base material preferably contains the (meth)acrylate monomer, if present, in a concentration of 15 mole% or less.
The above-mentioned adhesive base layer may be a copolymer containing a multifunctional monomer in a concentra-tion of 0.005 to 0.5~ by weight of the total amount of monomers therein.
In a more preferred embodiment, the multifunctional monomer is a di(meth)acrylate,;tri(meth)acrylate or tetra-(meth)acrylate or a mixture of two or more thereof.
Thus, the invention described here~ makes possible the objects of:
(a) providing a percutaneous administration type pharmaceutical preparation in tape form, which is excellent in the release of ISDN
dissolved in an adhesive base material at a high concentration, whereby to permit an effective administration of ISDN per unit area thereof;
(b) providing a percutaneous administration type pharmaceutical preparation in tape form, which is significantly less irritative to the skin;
(c) providing a percutaneous administration type pharmaceutical preparation in tape form, which is excellent in both release and transfer to the skin of the active ingredient thereby exhibiting an immediate pharmaceutical effect for angina pectoris, etc.;
l~S~S7 (d) providing a percutaneous administration type pharmaceutical preparation in tape form, which can maintaln a high concentration of ISDN in the blood per unit skin area, compared wi-th conventional pharmaceutical preparations, thereby exhibiting an excellent pharmaceutical effect with a small application area to the skin;
(e) providing a percutaneous administration type pharmaceutical preparation in tape form, which reduces unpleasant feeling on application to the skin, since the pharmaceutical effect can be exhibited with a minimized application area to the skin;
(f) providing a percutaneous administration type pharmaceutical preparation in tape form, which can be applied to the skin by a simple operation due to the minimized application area; and (g) providing a percutaneous administration type pharmaceutical preparation to minimize red spots on the skin due to a peculiar composition of the adhesive base material.
For a better understanding of the invention, embodi-ments will now be described, by way of example, with reference to the accompanying drawings, in which:
Figure 1 is a graphical representation showing the relationship between the application area of pharmaceutical preparations in tape form and the concentration of ISDN in the blood;
Figure 2 is a graphical representation showing the relationship between the thickness of the adhesive base layer of pharmaceutical preparatio~in tape form and the transfer o~ ISDN to the skin; and Figure 3 is a graphical representation showing the relationship between the amount of IS~N per 10 cm2 of the lZ~5157 adhesive base layer of pharmaceu-tical preparations in tape form and the concentration of ISDN in the blood.
N-vinyl-2-pyrolidone (VP) r the molecular weight of which is 111, has the following structural formula:
CH2 = CH
/N\
H2C C=O
\CH2 - CH2 A VP homopolymer, which is water-soluble, meets standard requirements for medical supplies.
It has been experimentally found by the inventors that the above-mentioned monomer is copolymerizable with a variety of acrylates and/or methacrylates and the resulting copolymers can serve as an adhesive base material. The desired copolymer comprises 2-ethylhexyl acrylate (EHA) and N-vinyl-2-pyrrolidone (VP), satisfying the requirements for an adhesive base material having properties such as adhesiveness, solubility of ISDN, release of ISDN and reduced irritation.
More specifically, the copolymer contains EHA in a concentra-tion of 45 mole% or more and VP in a concentration of 20 to 55 mole%. More preferably, it contains EHA in a concentration of 55 mole% or more and VP in a concentration of 30 to 45 mole%. If the amount of VP is less than 20 mole%, ISDN will not be effectively dissolved in the copolymer, i.e. the adhesive base material. If the amount of VP is greater than 55 mole%, the adhesiveness of the adhesive base material will be reduced.
Even though one or more other components, such as (meth)acrylate (i.e. r methacrylate and/or acrylate) monomers may be admixed in a concentration of 35 mole% or less, more preferably, 15 mole% or less, with the composition of EHA of 45 mole% or more and VP of 20% or more (more preferably, EHA
of 55 mole% or more and VP of 30 mole% or more), the desired properties and the abilities of the resulting adhesive base 12~5157 material are maintained. For the maintenance of excellent adhesiveness, a typical (meth)acrylate monomer for admixture therewith is an alkyl (meth)acrylate, which is, for example, propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, or lauryl methacrylate, but is not limited thereto.
The ISDN contained in the adhesive is present in a concentration of 10% by weight or more of the total weight of the adhesive base material plus the weight of ISDN, and preferably lO to 30% by weight, in a compatible state in the adhesive base material having the above-mentioned composition.
The ISDN is more preferably in a concentration of 13 to 25%
by weight, based on the overall adhesive base material. It should be understood that a concentration of lO to 30% by weight of ISDN contained in the adhesive base material is extremely high compared with a concentration of 8 parts by weight (i.e., 7.4% by weight) of ISDN in the pharmaceutical preparation disclosed in U.S. Patent No. 4,420,470, which was discussed above.
When a material dispersed in a compatible state into a matrix diffuses into or outside the matrix, its diffusion rate is generally significantly higher than that of a material existing in a powdered or crystalline state in the matrix. Thus, to eliminate the conventional drawbacks, it is essential that ISDN should exist within the adhesive base material in a compatible state with a concentration which is as close as possible to the saturated solubility concentration thereof. The terminology "the saturated solubility concentra-tion" used herein refers to an ISDN concentration high enoughsuch that the ISDN never crystallizes even though the adhesive base material containing a certain amount of ISDN is allowed to stand at room temperature for a long period of time. The terminology "a compatible state" used herein refers to a state in which ISDN exists in the saturated concentration or lower within the adhesive base material.
,.. . .
lZ~5~ S7 According to this invention, although the saturated concentration of ISDN in the adhesive base material depends upon the composition of the adhesive base material, ISDN may be contained in a slightly lower concentration than its saturated solubility concentration, in each of the adhesive base materials of various compositions. In light of the adhesive base material compositions described above, such a concentration of ISDN is in the range of 10~ by weight or more, preferably 10 to 30% by weigh~. It is more preferably in the range of 13 to 25% by weight of the base material.
For maintaining an excellent release level of ISDN, it is generally preferred that the amount of ISDN to be added to the base material is 80% or more of the satura-ted solubility concentration of ISDN with respect to the base material. It cannot be said that the base material which is best capable of dissolving ISDN in a high concentration therein is also most excellent in release of ISDN therefrom to the skin, since there are unresolved questions with regard to the determination of the distribution coefficient between the base material and the skin. Moreover, there has not been sufficient analysis of the phenomenon that the system varies depending upon factors such as perspiration during application of the tape to the skin. However, the base material according to this invention has, in general, proven superior in transfer of ISDN to the skin.
According to the present invention, a multi-functional monomer is preferably added as a component of the base material to copolymerize with the other monomer components, thereby producing slight or extremely slight linkages among the resulting polymers and resul-ting in increased internal cohesive properties of the resulting base material, so that none of the base material will remain on the skin when the tape is removed, regardless of skin conditions or the amount of perspiration on the skin. Furthermore, the use of such a multifunctional monomer as a component of the base material has no effect on the release of the active ingredient and lZ~SlS~
results in reduced irXitation of the resulting base material.
Examples of suitable multifunctional monomers are di~meth)-acrylates obtained by reaction of (meth)acrylic acid with polymethylene glycols such as hexamethylene glycol, octa-methylene glycol, etc.; di(meth)acrylates obtained byreaction of (meth)acrylic acid with polyalkylene glycols such as polyethylene glycol, polypropylene glycol, etc.; tri(meth~-acrylates such as trimethylolpropane tri(meth)acry~ate, glycerin tri~meth)acrylate, etc.; and tetra(meth)acrylates 10 such as pentaerythritol tetra(meth)acrylate etc. One or more multifunctional monomers are added to the other monomers to be copolymerized to form the base material, the added amount preferably being in the range of 0.005 to 0.5% by weight of the total amount of monomers to be copolymeriæed. If the 15 amount is less than 0.005~ by weight, the internal cohesive properties due to linkages will not be effectively attained.
If the amount is above 0.5~ by weight, the resulting base material will tend to gelatinize resulting in reduced diffu-sion and/or release of ISDN.
The flexible backing used in this invention is non-permeable to the active ingredient, i.e. ISDN. Examples of suitable backing materials include a single film composed of a polyester such as polyethylene terephthalate, etc., a polyamide such as nylon 6, etc., or a polyurethane; a lamina-25 ted film composed of a plurality of these single films; and a laminated ~ilm composed of one or more of these single films and a polyethylene (PE) film and/or an ethylene-vinyl acetate copolymer (EVA) film.
In general, crystallization of chemical compounds 30 occurs at the interface between foreign substances and the matrix containing the chemical compounds therein. In the pharmaceutical preparation according to this invention, although it appears that ISDN might crystallize at the inter-face between the adhesive base layer and -the backing due to its 35 structure, such crystallization has not been observed with any of the above-mentioned films when the amount of ISDN dissolved lZ453 57 in the base material is in a concentration of between 80%
(inclusive) and 100% (exclusive) of the saturated solubility concentration thereof. This phenomenon might be due to properties of the base material resulting from the composition as described above.
The percutaneous administration type pharmaceutical preparation in tape form according to this invention may be prepared as follows: -Given amounts of EHA and VP, and, if necessary, (meth)acrylate monomer(s) and/or multifunctional monomer(s)are admixed with ethyl acetate and/or other polymerization solvents, followed by a radical polymerization reaction at approximately 55C to 75C for 8 to 40 hours in a nitrogen gaseous atmosphere, resulting in a polymer having a solid content in an amount of 15 to 40% by weight. The viscosity of thispolymer is in the range of l,000 to 100,000 cps at a solid content of 25~ by weight, while the molecular weight (average molecular weight calculated in terms of stylene by a gel permeation chromatography) in in the range of lO0,000 to l,000,000. The residual EHA and VP monomers in the polymer amount to less than 2% by weight, respectively, based on the total weight of solid.
As a polymerization initiator, azobis derivatives, peroxides, etc. can be employed, but the process is not limited thereto. Examples of azobis derivatives include 2, 2'-azobis isobutyronitrile (AIBN); 1, l'-azobis cyclohexane-l-carbonitrile; and 2, 2'-azobis-2, 4-dimethyl-valeronitrile.
Examples of peroxides include benzoyl peroxide (BPO); lauroyl peroxide (LPO); and di-tertiary bu-tyl peroxide.
An ISDN solution which is prepared by dissolving ISDN in a solvent such as ethyl acetate is added to the adhesive base material prepared in the manner described above, resulting in a coating solution. The coating solution is then applied to a given thickness, to a release paper or a backing using a coating machine such as a direct coater or a reverse coater, etc. and then dried at a temperature of 70C or less lZ~51$7 to form an adhesive base layer containing ISDN in a concen-tration ranging from 10 to 30% by weight, the solvent being in a concentration of 100 ppm or less and only a trace (0.1~
by weight or less) of residual monomers remaining. The base 5 layer has a ball tack value of 15 or more, and a backing or a release paper is then laminated on the surface thereof, resulting in the desired percutaneous a~minis-tration type pharmaceutical preparation in tape form.
The following examples illustrate the invention.
10 Example 1 A separable flask was charged with 317.9 g (70 mole%) of EEIA, 82.1 g (30 mole~) of VP and 70.6 g of ethyl acetate to form a monomer solution having a monomer concen-tration of 85% by weight. The solution was heated at 60C
15 for 32 hours in a nitrogen a-tmosphere while adding dropwise thereto lauroyl peroxide as a polymerization initiator and ethyl acetate * as a polymerization solvent. Tb the resulting polymer, a certain amount of an ethyl acetate solution of ISDN was added resulting in a coating solution having solids (total ~so]ids of the polymP~r and th2 20 ISDN) content of 25% by weight and an ISDN solids content of 12~ by weight. In the same manner as described above, three further kinds of coating solution having a total solids content of 25% by weight and ISDN solids contents of 14, 16 and 18~ by weight, respectively, were prepared. Each 25 of these solutions was coated on a release paper having a thickness of 35 ~lm made of silicone-treated polyethylene terephthalate (PET) and dried -to form on the release paper an adhesive base layer having a thickness of 60~m, on which a backing of PET having a thickness of 9 ~m was placed, re-30 sulting in a pharmaceutical preparation in tape form.
Example 2 In the same manner as in Example 1, 215.2 g (45 mole~) of EEIA, 129.7 g ~45 mole%) of VP, 55.1 g (10 mole%) of decyl methacrylate and 0.01~ by weight (40.0 mg~
35 of trimethlolpropane triacrylate were subjected to polymer-ization. Using the resulting polymer, four coating solutions having ISDN solids contents of 22, 24, 26 and 28~ by weight, lZ~5~57 respectively, were prepared to obtain four different phar-maceutical preparations.
Example 3 In the same manner as in Example 1, 302.0 g (65 mole%) of EHA, 98.0 g (35 mole%) of VP and 0.02% by weight (80.0 mg) of hexamethyleneglycol aimethacrylate were used to prepare four coating solutions having ISDN solids con-tents of 14, 16, 18 and 20% by weight, respectively, result-ing in four different pharmaceutical preparations.
Example 4 In the same manner as in Example 1, 261.9 g (55 mole~) o EHA, 71.8 g (25 mole%) of VP, 66.3 g (20 mole%) of butyl acrylate and 0.01~ by weight (40.0 mg) of poly-propylene glycol diacrylate were used to prepare Ifour coat-ing solutions having ISDN solids contents of 10, 12, 14 and16% by weight, respec-tively, resulting in four different pharmaceutical preparations.
Control 1 In the same manner as in Example 1, 400.0 g (100 mole%) of EH~ was used to prepare three coating solutions having ISDN solids contents of 6, 8 and 10% by weight, re-spectively, resulting in three different pharmaceutical preparations.
Control 2 In the same manner as in Example 1, 188.7 g (35 mole~) of EHA and 211.3 g (65 mole%) of VP were used to pre-pare four coating solutions having ISDN solids contents of 24, 28, 32 and 36% by weight, respectively, resulting in four different pharmaceutical preparations.
Control 3 In the same manner as in Example 1, 93% by weight (372.0 g) of EHA and 7% by weight (28.0 g) of acrylic acid were used to prepare three coating solutions having ISDN
solids contents of 6, 8 and 10% by weight, respectively, resulting in three different pharmaceutical preparations.
Experiment 1 The ISDN-saturated solubilities and the adhesive-12f~5~57 nesses of the pharmaceutical preparations obtained above were examlned, and the results are shown in Table l.
The .ISDN-saturatec1 solubi,1,ities were determined as follows:
sy pee:Ling o~.~ the re].ease paper, the surface of the adhesive base l.ayer was exposed and several needle-sl1aped IS~N crysta].s were placed thereon. The surface was then covered again by the re]ease paper, enclosed in an aluminum laminated fi.1,m and malntained at room temperature .1,0 for one month, after which the growth of ISDN crystals was ob~erved. The symbol. "O" indicates that crystal. growth was not ob.served, the symbo.1. "~" indicates that crystal growth was i.nde~lr1it~, and the symbo~ "X" indicates that crystal yrowth was defil1ite1.y observed. The ISDN-saturated sol-l~ ubilities of each o~ the pharmaceutical preparations inExamp.1.es l to 4 and Controls l to 3 are given in parentheses in Tabl.e 1..
The ad}-lesiveness with respect to each o.~ the pharmaceutica]. preparations was examined just a.fter their manu~acture by a ball tack method a-t room temperature. The symbol.e "O" indlcates excel.lent adhesiveness and the symbol "X" indicates an in.~erior adhesiveness.
~245~L57 Table 1 _ .
ISDN Solids Crystal Adhesiveness Content (wt~) Growth Example 1 12 O (14) j 8 222- 8(26, 8 Example 2 2 6 ~ O
28 ~ O
_ Example 3 14 ~ 8 ~ 8 _ 20 I x o _ 12 O (lO 8 Example 4 14 X O
16 x O
6 O (8) O
Control 1 10 X oo .
Control 2 28 X (34) x _ _ Conerol 3 10 L (~) 1~5~57 Table 1 ind.icates that the pharmaceutical pre-paration of Control 2 was inEerior in adhesiveness.
Next, using the six different adhesive base ma-terials described in Examples 1 to 4 and Control 1 and 3, eighteen different pharmaceutical preparations as shown in Table 2, having an ISDN concentration of 90% of the ISDN-saturated solubilities which are given in parentheses in Table 1, were prepared in the same manner as in Example 1.Three sample preparations in each Example and Control were cut into squares, one of which had an area of lOcm2 with a thickness of 60 ~m, another of which had a thickness of 60 ~m and contained ISDN of 10 mg therein, and the last of which had an area of 10 cm2 and contained ISDN of 10 mg therein.
~Z4~i~57 Table 2 . __ ISDN Thickness of I5DN
Composition Sample Concentra- Base Layer Area Content No. tion (wt~)(~m) cm (mg) _ 1 ~ 1 60 10 i 7.6 Example 1 1 ~ 3 12.6 79 13.2 lg . 2 ~ 1 60 10 14.0 Example 2 2 ~ 2 23.4 60 7.1 10 2 ~ 3 43 10 10 . .
In a preferred embodiment, the adhesive ba~e material compri~es a copolymer containing EHA in a concentration of 55 mole~ or more and VP in a concentration of 30 to 45 1~45~57 mole%, and the concentration of ISDN in the adhesive base material is 13~ by weight or more.
The adhesive base material may also contain a (meth)-acrylate monomer, in a concentration of 35 mole~ or less, which comprises one or more monomers selected from the group consisting of propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate.
The adhesive base material preferably contains the (meth)acrylate monomer, if present, in a concentration of 15 mole% or less.
The above-mentioned adhesive base layer may be a copolymer containing a multifunctional monomer in a concentra-tion of 0.005 to 0.5~ by weight of the total amount of monomers therein.
In a more preferred embodiment, the multifunctional monomer is a di(meth)acrylate,;tri(meth)acrylate or tetra-(meth)acrylate or a mixture of two or more thereof.
Thus, the invention described here~ makes possible the objects of:
(a) providing a percutaneous administration type pharmaceutical preparation in tape form, which is excellent in the release of ISDN
dissolved in an adhesive base material at a high concentration, whereby to permit an effective administration of ISDN per unit area thereof;
(b) providing a percutaneous administration type pharmaceutical preparation in tape form, which is significantly less irritative to the skin;
(c) providing a percutaneous administration type pharmaceutical preparation in tape form, which is excellent in both release and transfer to the skin of the active ingredient thereby exhibiting an immediate pharmaceutical effect for angina pectoris, etc.;
l~S~S7 (d) providing a percutaneous administration type pharmaceutical preparation in tape form, which can maintaln a high concentration of ISDN in the blood per unit skin area, compared wi-th conventional pharmaceutical preparations, thereby exhibiting an excellent pharmaceutical effect with a small application area to the skin;
(e) providing a percutaneous administration type pharmaceutical preparation in tape form, which reduces unpleasant feeling on application to the skin, since the pharmaceutical effect can be exhibited with a minimized application area to the skin;
(f) providing a percutaneous administration type pharmaceutical preparation in tape form, which can be applied to the skin by a simple operation due to the minimized application area; and (g) providing a percutaneous administration type pharmaceutical preparation to minimize red spots on the skin due to a peculiar composition of the adhesive base material.
For a better understanding of the invention, embodi-ments will now be described, by way of example, with reference to the accompanying drawings, in which:
Figure 1 is a graphical representation showing the relationship between the application area of pharmaceutical preparations in tape form and the concentration of ISDN in the blood;
Figure 2 is a graphical representation showing the relationship between the thickness of the adhesive base layer of pharmaceutical preparatio~in tape form and the transfer o~ ISDN to the skin; and Figure 3 is a graphical representation showing the relationship between the amount of IS~N per 10 cm2 of the lZ~5157 adhesive base layer of pharmaceu-tical preparations in tape form and the concentration of ISDN in the blood.
N-vinyl-2-pyrolidone (VP) r the molecular weight of which is 111, has the following structural formula:
CH2 = CH
/N\
H2C C=O
\CH2 - CH2 A VP homopolymer, which is water-soluble, meets standard requirements for medical supplies.
It has been experimentally found by the inventors that the above-mentioned monomer is copolymerizable with a variety of acrylates and/or methacrylates and the resulting copolymers can serve as an adhesive base material. The desired copolymer comprises 2-ethylhexyl acrylate (EHA) and N-vinyl-2-pyrrolidone (VP), satisfying the requirements for an adhesive base material having properties such as adhesiveness, solubility of ISDN, release of ISDN and reduced irritation.
More specifically, the copolymer contains EHA in a concentra-tion of 45 mole% or more and VP in a concentration of 20 to 55 mole%. More preferably, it contains EHA in a concentration of 55 mole% or more and VP in a concentration of 30 to 45 mole%. If the amount of VP is less than 20 mole%, ISDN will not be effectively dissolved in the copolymer, i.e. the adhesive base material. If the amount of VP is greater than 55 mole%, the adhesiveness of the adhesive base material will be reduced.
Even though one or more other components, such as (meth)acrylate (i.e. r methacrylate and/or acrylate) monomers may be admixed in a concentration of 35 mole% or less, more preferably, 15 mole% or less, with the composition of EHA of 45 mole% or more and VP of 20% or more (more preferably, EHA
of 55 mole% or more and VP of 30 mole% or more), the desired properties and the abilities of the resulting adhesive base 12~5157 material are maintained. For the maintenance of excellent adhesiveness, a typical (meth)acrylate monomer for admixture therewith is an alkyl (meth)acrylate, which is, for example, propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, or lauryl methacrylate, but is not limited thereto.
The ISDN contained in the adhesive is present in a concentration of 10% by weight or more of the total weight of the adhesive base material plus the weight of ISDN, and preferably lO to 30% by weight, in a compatible state in the adhesive base material having the above-mentioned composition.
The ISDN is more preferably in a concentration of 13 to 25%
by weight, based on the overall adhesive base material. It should be understood that a concentration of lO to 30% by weight of ISDN contained in the adhesive base material is extremely high compared with a concentration of 8 parts by weight (i.e., 7.4% by weight) of ISDN in the pharmaceutical preparation disclosed in U.S. Patent No. 4,420,470, which was discussed above.
When a material dispersed in a compatible state into a matrix diffuses into or outside the matrix, its diffusion rate is generally significantly higher than that of a material existing in a powdered or crystalline state in the matrix. Thus, to eliminate the conventional drawbacks, it is essential that ISDN should exist within the adhesive base material in a compatible state with a concentration which is as close as possible to the saturated solubility concentration thereof. The terminology "the saturated solubility concentra-tion" used herein refers to an ISDN concentration high enoughsuch that the ISDN never crystallizes even though the adhesive base material containing a certain amount of ISDN is allowed to stand at room temperature for a long period of time. The terminology "a compatible state" used herein refers to a state in which ISDN exists in the saturated concentration or lower within the adhesive base material.
,.. . .
lZ~5~ S7 According to this invention, although the saturated concentration of ISDN in the adhesive base material depends upon the composition of the adhesive base material, ISDN may be contained in a slightly lower concentration than its saturated solubility concentration, in each of the adhesive base materials of various compositions. In light of the adhesive base material compositions described above, such a concentration of ISDN is in the range of 10~ by weight or more, preferably 10 to 30% by weigh~. It is more preferably in the range of 13 to 25% by weight of the base material.
For maintaining an excellent release level of ISDN, it is generally preferred that the amount of ISDN to be added to the base material is 80% or more of the satura-ted solubility concentration of ISDN with respect to the base material. It cannot be said that the base material which is best capable of dissolving ISDN in a high concentration therein is also most excellent in release of ISDN therefrom to the skin, since there are unresolved questions with regard to the determination of the distribution coefficient between the base material and the skin. Moreover, there has not been sufficient analysis of the phenomenon that the system varies depending upon factors such as perspiration during application of the tape to the skin. However, the base material according to this invention has, in general, proven superior in transfer of ISDN to the skin.
According to the present invention, a multi-functional monomer is preferably added as a component of the base material to copolymerize with the other monomer components, thereby producing slight or extremely slight linkages among the resulting polymers and resul-ting in increased internal cohesive properties of the resulting base material, so that none of the base material will remain on the skin when the tape is removed, regardless of skin conditions or the amount of perspiration on the skin. Furthermore, the use of such a multifunctional monomer as a component of the base material has no effect on the release of the active ingredient and lZ~SlS~
results in reduced irXitation of the resulting base material.
Examples of suitable multifunctional monomers are di~meth)-acrylates obtained by reaction of (meth)acrylic acid with polymethylene glycols such as hexamethylene glycol, octa-methylene glycol, etc.; di(meth)acrylates obtained byreaction of (meth)acrylic acid with polyalkylene glycols such as polyethylene glycol, polypropylene glycol, etc.; tri(meth~-acrylates such as trimethylolpropane tri(meth)acry~ate, glycerin tri~meth)acrylate, etc.; and tetra(meth)acrylates 10 such as pentaerythritol tetra(meth)acrylate etc. One or more multifunctional monomers are added to the other monomers to be copolymerized to form the base material, the added amount preferably being in the range of 0.005 to 0.5% by weight of the total amount of monomers to be copolymeriæed. If the 15 amount is less than 0.005~ by weight, the internal cohesive properties due to linkages will not be effectively attained.
If the amount is above 0.5~ by weight, the resulting base material will tend to gelatinize resulting in reduced diffu-sion and/or release of ISDN.
The flexible backing used in this invention is non-permeable to the active ingredient, i.e. ISDN. Examples of suitable backing materials include a single film composed of a polyester such as polyethylene terephthalate, etc., a polyamide such as nylon 6, etc., or a polyurethane; a lamina-25 ted film composed of a plurality of these single films; and a laminated ~ilm composed of one or more of these single films and a polyethylene (PE) film and/or an ethylene-vinyl acetate copolymer (EVA) film.
In general, crystallization of chemical compounds 30 occurs at the interface between foreign substances and the matrix containing the chemical compounds therein. In the pharmaceutical preparation according to this invention, although it appears that ISDN might crystallize at the inter-face between the adhesive base layer and -the backing due to its 35 structure, such crystallization has not been observed with any of the above-mentioned films when the amount of ISDN dissolved lZ453 57 in the base material is in a concentration of between 80%
(inclusive) and 100% (exclusive) of the saturated solubility concentration thereof. This phenomenon might be due to properties of the base material resulting from the composition as described above.
The percutaneous administration type pharmaceutical preparation in tape form according to this invention may be prepared as follows: -Given amounts of EHA and VP, and, if necessary, (meth)acrylate monomer(s) and/or multifunctional monomer(s)are admixed with ethyl acetate and/or other polymerization solvents, followed by a radical polymerization reaction at approximately 55C to 75C for 8 to 40 hours in a nitrogen gaseous atmosphere, resulting in a polymer having a solid content in an amount of 15 to 40% by weight. The viscosity of thispolymer is in the range of l,000 to 100,000 cps at a solid content of 25~ by weight, while the molecular weight (average molecular weight calculated in terms of stylene by a gel permeation chromatography) in in the range of lO0,000 to l,000,000. The residual EHA and VP monomers in the polymer amount to less than 2% by weight, respectively, based on the total weight of solid.
As a polymerization initiator, azobis derivatives, peroxides, etc. can be employed, but the process is not limited thereto. Examples of azobis derivatives include 2, 2'-azobis isobutyronitrile (AIBN); 1, l'-azobis cyclohexane-l-carbonitrile; and 2, 2'-azobis-2, 4-dimethyl-valeronitrile.
Examples of peroxides include benzoyl peroxide (BPO); lauroyl peroxide (LPO); and di-tertiary bu-tyl peroxide.
An ISDN solution which is prepared by dissolving ISDN in a solvent such as ethyl acetate is added to the adhesive base material prepared in the manner described above, resulting in a coating solution. The coating solution is then applied to a given thickness, to a release paper or a backing using a coating machine such as a direct coater or a reverse coater, etc. and then dried at a temperature of 70C or less lZ~51$7 to form an adhesive base layer containing ISDN in a concen-tration ranging from 10 to 30% by weight, the solvent being in a concentration of 100 ppm or less and only a trace (0.1~
by weight or less) of residual monomers remaining. The base 5 layer has a ball tack value of 15 or more, and a backing or a release paper is then laminated on the surface thereof, resulting in the desired percutaneous a~minis-tration type pharmaceutical preparation in tape form.
The following examples illustrate the invention.
10 Example 1 A separable flask was charged with 317.9 g (70 mole%) of EEIA, 82.1 g (30 mole~) of VP and 70.6 g of ethyl acetate to form a monomer solution having a monomer concen-tration of 85% by weight. The solution was heated at 60C
15 for 32 hours in a nitrogen a-tmosphere while adding dropwise thereto lauroyl peroxide as a polymerization initiator and ethyl acetate * as a polymerization solvent. Tb the resulting polymer, a certain amount of an ethyl acetate solution of ISDN was added resulting in a coating solution having solids (total ~so]ids of the polymP~r and th2 20 ISDN) content of 25% by weight and an ISDN solids content of 12~ by weight. In the same manner as described above, three further kinds of coating solution having a total solids content of 25% by weight and ISDN solids contents of 14, 16 and 18~ by weight, respectively, were prepared. Each 25 of these solutions was coated on a release paper having a thickness of 35 ~lm made of silicone-treated polyethylene terephthalate (PET) and dried -to form on the release paper an adhesive base layer having a thickness of 60~m, on which a backing of PET having a thickness of 9 ~m was placed, re-30 sulting in a pharmaceutical preparation in tape form.
Example 2 In the same manner as in Example 1, 215.2 g (45 mole~) of EEIA, 129.7 g ~45 mole%) of VP, 55.1 g (10 mole%) of decyl methacrylate and 0.01~ by weight (40.0 mg~
35 of trimethlolpropane triacrylate were subjected to polymer-ization. Using the resulting polymer, four coating solutions having ISDN solids contents of 22, 24, 26 and 28~ by weight, lZ~5~57 respectively, were prepared to obtain four different phar-maceutical preparations.
Example 3 In the same manner as in Example 1, 302.0 g (65 mole%) of EHA, 98.0 g (35 mole%) of VP and 0.02% by weight (80.0 mg) of hexamethyleneglycol aimethacrylate were used to prepare four coating solutions having ISDN solids con-tents of 14, 16, 18 and 20% by weight, respectively, result-ing in four different pharmaceutical preparations.
Example 4 In the same manner as in Example 1, 261.9 g (55 mole~) o EHA, 71.8 g (25 mole%) of VP, 66.3 g (20 mole%) of butyl acrylate and 0.01~ by weight (40.0 mg) of poly-propylene glycol diacrylate were used to prepare Ifour coat-ing solutions having ISDN solids contents of 10, 12, 14 and16% by weight, respec-tively, resulting in four different pharmaceutical preparations.
Control 1 In the same manner as in Example 1, 400.0 g (100 mole%) of EH~ was used to prepare three coating solutions having ISDN solids contents of 6, 8 and 10% by weight, re-spectively, resulting in three different pharmaceutical preparations.
Control 2 In the same manner as in Example 1, 188.7 g (35 mole~) of EHA and 211.3 g (65 mole%) of VP were used to pre-pare four coating solutions having ISDN solids contents of 24, 28, 32 and 36% by weight, respectively, resulting in four different pharmaceutical preparations.
Control 3 In the same manner as in Example 1, 93% by weight (372.0 g) of EHA and 7% by weight (28.0 g) of acrylic acid were used to prepare three coating solutions having ISDN
solids contents of 6, 8 and 10% by weight, respectively, resulting in three different pharmaceutical preparations.
Experiment 1 The ISDN-saturated solubilities and the adhesive-12f~5~57 nesses of the pharmaceutical preparations obtained above were examlned, and the results are shown in Table l.
The .ISDN-saturatec1 solubi,1,ities were determined as follows:
sy pee:Ling o~.~ the re].ease paper, the surface of the adhesive base l.ayer was exposed and several needle-sl1aped IS~N crysta].s were placed thereon. The surface was then covered again by the re]ease paper, enclosed in an aluminum laminated fi.1,m and malntained at room temperature .1,0 for one month, after which the growth of ISDN crystals was ob~erved. The symbol. "O" indicates that crystal. growth was not ob.served, the symbo.1. "~" indicates that crystal growth was i.nde~lr1it~, and the symbo~ "X" indicates that crystal yrowth was defil1ite1.y observed. The ISDN-saturated sol-l~ ubilities of each o~ the pharmaceutical preparations inExamp.1.es l to 4 and Controls l to 3 are given in parentheses in Tabl.e 1..
The ad}-lesiveness with respect to each o.~ the pharmaceutica]. preparations was examined just a.fter their manu~acture by a ball tack method a-t room temperature. The symbol.e "O" indlcates excel.lent adhesiveness and the symbol "X" indicates an in.~erior adhesiveness.
~245~L57 Table 1 _ .
ISDN Solids Crystal Adhesiveness Content (wt~) Growth Example 1 12 O (14) j 8 222- 8(26, 8 Example 2 2 6 ~ O
28 ~ O
_ Example 3 14 ~ 8 ~ 8 _ 20 I x o _ 12 O (lO 8 Example 4 14 X O
16 x O
6 O (8) O
Control 1 10 X oo .
Control 2 28 X (34) x _ _ Conerol 3 10 L (~) 1~5~57 Table 1 ind.icates that the pharmaceutical pre-paration of Control 2 was inEerior in adhesiveness.
Next, using the six different adhesive base ma-terials described in Examples 1 to 4 and Control 1 and 3, eighteen different pharmaceutical preparations as shown in Table 2, having an ISDN concentration of 90% of the ISDN-saturated solubilities which are given in parentheses in Table 1, were prepared in the same manner as in Example 1.Three sample preparations in each Example and Control were cut into squares, one of which had an area of lOcm2 with a thickness of 60 ~m, another of which had a thickness of 60 ~m and contained ISDN of 10 mg therein, and the last of which had an area of 10 cm2 and contained ISDN of 10 mg therein.
~Z4~i~57 Table 2 . __ ISDN Thickness of I5DN
Composition Sample Concentra- Base Layer Area Content No. tion (wt~)(~m) cm (mg) _ 1 ~ 1 60 10 i 7.6 Example 1 1 ~ 3 12.6 79 13.2 lg . 2 ~ 1 60 10 14.0 Example 2 2 ~ 2 23.4 60 7.1 10 2 ~ 3 43 10 10 . .
3 - 1 60 10 9.2 Example 3 1 3 ~ 2315.3 6~ 10o 9 10 _
4 ~ 1 60 10 6.
Example 44 ~ 3 10.8 603 10 1O
Example 44 ~ 3 10.8 603 10 1O
5 ~ 1 60 10 4.3 5 - 2~ ~ 139 23.1 l~
6 - 1 60 10 4.3 5 - 2 ~ l39 l3.l l~
lZ~SlS7 Table 2 indicates that the required surface area of each of the preparations according to this invention is extremely small when compared wi-th that of the control pre-parations when sample preparations-of the same ISDN content and the same thickness of the base materials are prepared, and that the amount o~ ISDN administered according to this invention becomes extremely high when sample preparations of the same area and the same thickness of the base layer are compared to those of the control. Using these preparations, 10 the following Experiments 2 to 5 were carried out.
Experiment 2 Each of six different pharmaceutical preparations (Sample Nos. 1-2, 2-2, 3-2, 4-2, 5-2 and 6-2) containing ISDN of 10 mg was applied -to the back of a rabbit (Japanese 15 White sp.) on a portion where the hair had been removed.
After a predetermined period of time (i.e., 1, 4, 8 and 24 hours), a certain amountof blood was collected and subjected to a determination oE the ISDN concentration therein. This experiment was repeated three times. The results are shown 20 in Figure 1, indicating that the sample preparations accord-ing to this invention are in approximately the same concen-tration of ISDN in the blood as the control preparation while each oE the pharmaceutical preparations of Examples 1-4 according to this invention has an area 1/2 to 1/3 the 25 control preparations of Controls 1 and 3, thereby permitting a reduction of the application area and thus a simplified application of the preparation.
Experiment 3 Each of the five pharmaceutical preparations 30 (Sample Nos. 1-3, 2-3, 3-3, 4-3 and 5-3) having an area of 10 cm2 and an ISDN content of 10 mg was applied to the back and side of a rabbit lJapanese White sp.) on portions where the hair had been removed. After a predetermined period of time ~i.e., 2, 8 and 24 hours), each oF the 35 preparations was removed and subjected to an ISDN extrac-tion treatment with methanol to extract ISDN, and then measured by liquid chromatography. The determination ,~ :
~'~
~Z~ 57 values were subtracted from 10 mg of the initial ISDN con-tents, resulting in the transfer values of ISDN to the skin.
The determination of the transfer of ISDN to the skin was re-peated three times. The results are shown in Figure 2, in-dicating that the transfer is approximately inversely pro-portional to the thickness of the adhesive base layer and that the preparations of Examples 1 to 4 having a thin adhesive base layer are excellent in bioavailability.
Experiment 4 Each of the five pharmaceutical preparations (Sample Nos.
1-], 2-1, 3-1, 4-1 and 6-1), having an area of lOcm2 and a base layer thickness of 60 ~m, and a lOcm2 peace of Blenderm ~ surgical tape were applied to a rabbit in the same manner as in Experiment 3. After 24 hours, all of the tapes were removed to determine irritation to the skin and the residual amount of the adhesive base material. These procedures were repeated four times.
The irritation test was carried out by evaluating the intensity of red spots on the skin JUSt after removal of the tapes and again at 48 hours thereafter. The eval-uation of marks is as follows: the mark zero (0) indicatesthat red spots were not observed at all; the mark 1 in-dicates that traces of red spot were observed; the mark 2 in-dicates that red spots were clearly observed, the mark 3 in-! dicates that slightly cardinal red spots were observed; and the mark 4 indicates that cardinal red spots were observed.In this experiment, neither incrustations nor edemata were observed on the skin.
The total evaluation marks were averaged to rep-resent the irritation indexes of each of the evaluated tapes and are shown in Table 3.
Table 3 Tape Example Example Example Example Control Surgical 1 2 3 4 3 Tape Index of Irritation to 1.501.50 1.251.25 1.75 1.25 the skin ;, ~'' ,; . .,~
1;2~51S7 Table 3 indicates that the pharmaceutical prepar-ations according to this invention result in significantly reduced irritation to the skin because their irritation in-dexes are approximately equal to those of the control sur-gical tape.
A test of the residual amount of adhesive wascarried out just after removal of the tapes. The evaluation marks are as Eollows: the mark zero (0) indicates that the residual amount was zero, the mark l indicates that the residual amount was slight, the mark 2 indicates that residual adhesive was observed on the skin corresponding to the corners and/or the edges of the tape, and the mark 3 indicates that residual adhesive was observed on the skin corresponding to a half or more of the area of the tape.
15The total evaluation marks were averaged to rep-resent the residual adhesive indexes of each of the eval-uated tapes and are shown in Table 4.
Table 4 20 TapeE ~ ple Example Example E~lple Control Surgical 1 2 3 4 3 Tape Index of Residual 0.75 0 0 0 0.50 0.50 25 Adhesive Table 4 indicates -that the pharmaceutical pre-parations according to this invention exhibit excellent ad-hesiveness and reduced residual amounts of the adhesive, and especially, the pharmaceutical preparations in Examples 2, 3 and 4, wherein a multi-functional monomer was used to pro-duce slight or extremely slight linkages among the polymers, which did not leave any adhesive on the skin at all.
Experiment 5 Each of the five pharmaceutical preparatior.s (Sample Nos. 1-1, 2-l, 3-l, 4-1 and 6-l) (all having the same thickness but varying in ISDN content) was applied lZ~SlS7 to the back of a rabbit on a portion where the hair had been removed. After a predetermined period of time (i.e., 1, 6 and 24 hours), the concentration of ISDN in the blood was measured and the results of this are shown in Figure 3. The determination was repeated three times.
Figure 3 shows that the pharmaceutical preparations according to this invention are capable of affording an in-creased concentration of ISDN in the blood compared with the control pharmaceutical preparation when they have the same area and thickness as the control.
It is understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the scope and spiri-t oE
this invention. Accordingly, it is not intendedlthat the scope of the claims appended hereto be limited to the de-scription as set forth herein, but rather that the claims be construed as encompassing all the features oE patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which this invention pertains.
, .
'I
lZ~SlS7 Table 2 indicates that the required surface area of each of the preparations according to this invention is extremely small when compared wi-th that of the control pre-parations when sample preparations-of the same ISDN content and the same thickness of the base materials are prepared, and that the amount o~ ISDN administered according to this invention becomes extremely high when sample preparations of the same area and the same thickness of the base layer are compared to those of the control. Using these preparations, 10 the following Experiments 2 to 5 were carried out.
Experiment 2 Each of six different pharmaceutical preparations (Sample Nos. 1-2, 2-2, 3-2, 4-2, 5-2 and 6-2) containing ISDN of 10 mg was applied -to the back of a rabbit (Japanese 15 White sp.) on a portion where the hair had been removed.
After a predetermined period of time (i.e., 1, 4, 8 and 24 hours), a certain amountof blood was collected and subjected to a determination oE the ISDN concentration therein. This experiment was repeated three times. The results are shown 20 in Figure 1, indicating that the sample preparations accord-ing to this invention are in approximately the same concen-tration of ISDN in the blood as the control preparation while each oE the pharmaceutical preparations of Examples 1-4 according to this invention has an area 1/2 to 1/3 the 25 control preparations of Controls 1 and 3, thereby permitting a reduction of the application area and thus a simplified application of the preparation.
Experiment 3 Each of the five pharmaceutical preparations 30 (Sample Nos. 1-3, 2-3, 3-3, 4-3 and 5-3) having an area of 10 cm2 and an ISDN content of 10 mg was applied to the back and side of a rabbit lJapanese White sp.) on portions where the hair had been removed. After a predetermined period of time ~i.e., 2, 8 and 24 hours), each oF the 35 preparations was removed and subjected to an ISDN extrac-tion treatment with methanol to extract ISDN, and then measured by liquid chromatography. The determination ,~ :
~'~
~Z~ 57 values were subtracted from 10 mg of the initial ISDN con-tents, resulting in the transfer values of ISDN to the skin.
The determination of the transfer of ISDN to the skin was re-peated three times. The results are shown in Figure 2, in-dicating that the transfer is approximately inversely pro-portional to the thickness of the adhesive base layer and that the preparations of Examples 1 to 4 having a thin adhesive base layer are excellent in bioavailability.
Experiment 4 Each of the five pharmaceutical preparations (Sample Nos.
1-], 2-1, 3-1, 4-1 and 6-1), having an area of lOcm2 and a base layer thickness of 60 ~m, and a lOcm2 peace of Blenderm ~ surgical tape were applied to a rabbit in the same manner as in Experiment 3. After 24 hours, all of the tapes were removed to determine irritation to the skin and the residual amount of the adhesive base material. These procedures were repeated four times.
The irritation test was carried out by evaluating the intensity of red spots on the skin JUSt after removal of the tapes and again at 48 hours thereafter. The eval-uation of marks is as follows: the mark zero (0) indicatesthat red spots were not observed at all; the mark 1 in-dicates that traces of red spot were observed; the mark 2 in-dicates that red spots were clearly observed, the mark 3 in-! dicates that slightly cardinal red spots were observed; and the mark 4 indicates that cardinal red spots were observed.In this experiment, neither incrustations nor edemata were observed on the skin.
The total evaluation marks were averaged to rep-resent the irritation indexes of each of the evaluated tapes and are shown in Table 3.
Table 3 Tape Example Example Example Example Control Surgical 1 2 3 4 3 Tape Index of Irritation to 1.501.50 1.251.25 1.75 1.25 the skin ;, ~'' ,; . .,~
1;2~51S7 Table 3 indicates that the pharmaceutical prepar-ations according to this invention result in significantly reduced irritation to the skin because their irritation in-dexes are approximately equal to those of the control sur-gical tape.
A test of the residual amount of adhesive wascarried out just after removal of the tapes. The evaluation marks are as Eollows: the mark zero (0) indicates that the residual amount was zero, the mark l indicates that the residual amount was slight, the mark 2 indicates that residual adhesive was observed on the skin corresponding to the corners and/or the edges of the tape, and the mark 3 indicates that residual adhesive was observed on the skin corresponding to a half or more of the area of the tape.
15The total evaluation marks were averaged to rep-resent the residual adhesive indexes of each of the eval-uated tapes and are shown in Table 4.
Table 4 20 TapeE ~ ple Example Example E~lple Control Surgical 1 2 3 4 3 Tape Index of Residual 0.75 0 0 0 0.50 0.50 25 Adhesive Table 4 indicates -that the pharmaceutical pre-parations according to this invention exhibit excellent ad-hesiveness and reduced residual amounts of the adhesive, and especially, the pharmaceutical preparations in Examples 2, 3 and 4, wherein a multi-functional monomer was used to pro-duce slight or extremely slight linkages among the polymers, which did not leave any adhesive on the skin at all.
Experiment 5 Each of the five pharmaceutical preparatior.s (Sample Nos. 1-1, 2-l, 3-l, 4-1 and 6-l) (all having the same thickness but varying in ISDN content) was applied lZ~SlS7 to the back of a rabbit on a portion where the hair had been removed. After a predetermined period of time (i.e., 1, 6 and 24 hours), the concentration of ISDN in the blood was measured and the results of this are shown in Figure 3. The determination was repeated three times.
Figure 3 shows that the pharmaceutical preparations according to this invention are capable of affording an in-creased concentration of ISDN in the blood compared with the control pharmaceutical preparation when they have the same area and thickness as the control.
It is understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the scope and spiri-t oE
this invention. Accordingly, it is not intendedlthat the scope of the claims appended hereto be limited to the de-scription as set forth herein, but rather that the claims be construed as encompassing all the features oE patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which this invention pertains.
, .
'I
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A percutaneous administration type pharmaceutical preparation in tape form comprising a flexible backing, which is non-permeable to the active ingredient, and an adhesive base layer formed on said flexible backing; the adhesive base layer consisting essentially of an adhesive base material and an active ingredient compatible with said adhesive base material, wherein the adhesive base material is a copolymer containing 2-ethylhexyl acrylate (EHA) in a concentration of 45 to 80 mole %, a (meth)acrylate monomer in a concentration of 0 to 35 mole %, which comprises one or more members selected from the group consisting of propyl acrylate, butyl acrylate, hexyl acrylate, 2-ethyl butyl acrylate, heptyl acylate, octyl acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate, and N-vinyl-2-pyrrolidone (VP) in a concentration of 20 to 55 mole %, with the sum of the mole % of EHA, (meth)acrylate and VP
being 100, and with the EHA/VP ratio in mole % being in the range of from 80/20 to 45/55, and the active ingredient is isosorbide denitrate (ISDN) which is present in said adhesive base material in a concentration of 10 to 30% by weight and in a concentration of 80 to 100 (exclusive) % of the saturated solubility concentration of ISDN in said adhesive base material.
being 100, and with the EHA/VP ratio in mole % being in the range of from 80/20 to 45/55, and the active ingredient is isosorbide denitrate (ISDN) which is present in said adhesive base material in a concentration of 10 to 30% by weight and in a concentration of 80 to 100 (exclusive) % of the saturated solubility concentration of ISDN in said adhesive base material.
2. A pharmaceutical preparation according to claim 1, wherein the adhesive base material is a copolymer containing EHA in a concentration of 55 to 70 mole %, a (meth)acrylate monomer in a concentration of 0 to 15 mole % and VP in a concentration of 30 to 45 mole %, with the sum of the mole % of EHA, (meth)acrylate and VP being 100 and with the EHA/VP ratio in mole % being in the range of from 70/30 to 55/45, and the concentration of ISDN in the adhesive base material is 13 to 25% by weight and is 80 to 100 (exclusive) % of the saturated solubility concentration of ISDN in said adhesive base material.
3. A pharmaceutical preparation according to claim 1 or 2, wherein said adhesive base material is a copolymer containing no (meth) acrylate monomer.
4. A pharmaceutical preparation according to claim 1, wherein the adhesive base material is a copolymer containing a multifunctional monomer in a concentration of 0.005 to 0.5% by weight based on the total amount of monomers therein, said multifunctional monomer being one or more members selected from the group consisting of di ( meth ) acrylates, tri ( meth ) acrylates and tetra(meth)acrylates.
5. A pharmaceutical preparation according to claim 4, wherein the multifunctional monomer is a di(meth)acrylate.
6. A pharmaceutical preparation according to claim 5, wherein the di(meth)acrylate is obtained by reaction of an acrylate with a polymethylene glycol and/or by the reaction of an acrylate with a polyalkylene glycol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000466151A CA1245157A (en) | 1984-10-23 | 1984-10-23 | Percutaneous administration type pharmaceutical preparation in tape form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000466151A CA1245157A (en) | 1984-10-23 | 1984-10-23 | Percutaneous administration type pharmaceutical preparation in tape form |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1245157A true CA1245157A (en) | 1988-11-22 |
Family
ID=4128982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000466151A Expired CA1245157A (en) | 1984-10-23 | 1984-10-23 | Percutaneous administration type pharmaceutical preparation in tape form |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1245157A (en) |
-
1984
- 1984-10-23 CA CA000466151A patent/CA1245157A/en not_active Expired
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