JP2693212B2 - Tape preparation for disease treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a tape preparation for treating a disease, which is intended to transdermally administer a basic drug having a free base structure into a living body.

<Prior art> In recent years, as a preparation for treating or preventing a disease by administering a drug into a living body, drug metabolism due to the first-pass effect of the liver and various side effects can be prevented, and the drug can be sustained for a long time. Attention has been paid to transdermal preparations that can be administered to the skin. In particular, since the administration work is easy and the dose can be strictly controlled among them, a tape preparation containing a drug in an adhesive has been actively developed.

Since such a tape preparation is used by sticking an adhesive layer containing a drug on the skin surface, it prevents the decrease of the drug content in the adhesive (drug stability) and releases the drug from the adhesive. Various properties such as adhesion to the skin surface (adhesiveness), appropriate cohesiveness for eliminating adhesive residue on the skin surface, and non-irritating property to the skin are required. In other words, when developing a tape formulation, it is extremely important to study the chemical and physical properties of the adhesive used, the chemical properties of the drug contained in the adhesive, and the interaction of these combinations. However, the fact is that almost no tape preparation satisfying all the above-mentioned required characteristics has been obtained.

Further, the drug is usually provided in a form such as a free base structure or a salt structure, but it is said that the drug having a free base structure is inferior in drug stability and has large skin irritation. Moreover, since it has a lower melting point than that of a drug having a salt structure, when it is contained in the pressure-sensitive adhesive, it has a problem that it exhibits a plasticizing action to lower the cohesive force.

<Problems to be Solved by the Invention> According to the present invention, a drug having a free base structure is contained in an adhesive with good stability, and there is no decrease in cohesive force of the adhesive due to plasticizing action of the drug or skin irritation. It is an object of the present invention to provide a tape preparation excellent in the release property of

<Means for Solving the Problems> As a result of intensive studies conducted by the present inventors to achieve the above object, when a basic drug is used among drugs having a free base structure, it is combined with an adhesive having a specific composition. As a result, it was found that a tape formulation which relatively satisfies the above-mentioned required characteristics was obtained, and the present invention was completed.

That is, the tape preparation for disease treatment of the present invention is a tape preparation obtained by laminating a drug-containing pressure-sensitive adhesive layer containing a basic drug having a free base structure in a pressure-sensitive adhesive on a flexible support. , A part of or all of the carboxyl groups of a copolymer obtained from an alkyl acrylate ester having an alkyl group having 4 to 12 carbon atoms and a monomer having a carboxyl group in the molecule by a basic substance It is a copolymer which is inactivated.

In the present invention, by using the above-mentioned copolymer as the adhesive, the drug is stably contained, the release property is remarkably improved, and the drug can be quantitatively and continuously released over a long period of time.

The adhesive used in the present invention has a function of closely fixing the tape preparation on the skin surface and releasing the contained basic drug having a free base structure to the skin surface. As such an adhesive, it is preferable to use the above specific copolymer so that the drug can be stably retained without being decomposed.

The alkyl acrylate used for forming the above copolymer has 4 carbon atoms from the viewpoint of skin adhesion.
It is preferable to use one or more types of (meth) acrylic acid alkyl esters having 1 to 12 alkyl groups (including cyclic alkyl groups such as cyclohexyl groups) as the main component monomer, usually 50% by weight or more. Blend to prepare a copolymer.

Further, in order to reduce the reactivity between the copolymer and the drug as much as possible, it is generally preferable that the adhesive does not have a polar functional group, but it is surprising that the inventors of the present invention make repeated studies. The above-mentioned copolymer, that is, a pressure-sensitive adhesive comprising an acrylic copolymer having a carboxyl group as a functional group in the molecule and a part or all of this functional group being inactivated by a basic substance is free. It has been found that the basic drug having a basic structure does not impair the stability and exhibits a quantitative sustained release property for a long time, that is, a so-called pseudo zero-order release property.

Such an acrylic copolymer uses the alkyl acrylate as a main component monomer, and
By copolymerizing one or more monomers having a carboxyl group in the molecule such as (meth) acrylic acid, (iso) crotonic acid, fumaric acid, maleic acid, and itaconic acid, and further adding a basic substance. Obtainable. Upon copolymerization, 0.5 to 20% by weight, preferably 2 to 10% by weight of the above-mentioned monomer having a carboxyl group in the molecule.
Blend in the range of. If the amount is less than 0.5% by weight, the sustained release property, especially the pseudo zeroth order release property may be insufficient, and if it exceeds 20% by weight, the cohesive force of the adhesive becomes too high and the skin adhesiveness deteriorates. May occur.

In addition, as the third component monomer in the acrylic copolymer having the inactivated carboxyl group in the molecule,
Styrene, (meth) acrylic acid phenyl ester, (meth) acrylic acid alkyl ester having an alkyl group having 4 or less carbon atoms, for example, a non-functional monomer such as (meth) acrylic acid methyl ester, ethyl ester, propyl ester, etc. The body can also be copolymerized.

When the acrylic copolymer having the inactivated carboxyl group in the molecule is used as a pressure-sensitive adhesive, a basic drug having a free base structure is temporarily captured in the pressure-sensitive adhesive as described later. Therefore, by incorporating the drug in an amount greater than the number of moles of the functional group in the adhesive, the drug not captured is released at an early stage to exert a rapid effect, and thereafter, the captured drug is gradually quantitatively pseudo zero order. As it is released, it exerts a sustained pharmacological effect over a long period of time. Further, when the drug amount is less than the number of moles of the functional group in the adhesive, it does not have a rapid effect, but since the trapped drug is continuously released by the pseudo zero-order release,
It is an effective tape formulation for drugs with a low effective blood concentration range.

In the present invention, when a tape preparation using an acrylic copolymer having a carboxyl group in the molecule as an adhesive is applied to the skin surface, skin irritation or the like may occur. , A hydroxide of alkaline earth metal such as calcium, and a basic substance such as a compound having a quaternary amine such as ammonia or ethanolamine are added to inactivate the carboxyl group in the adhesive. In this case, the amount of the basic substance blended is not more than the number of moles of the carboxyl group in the adhesive.

By changing the compounding amount of the basic substance, the initial release amount of the drug can be increased to give a rapid effect, and the release property of the drug can be freely changed. In addition, when a basic substance is added, the cohesiveness of the pressure-sensitive adhesive is increased and the hydrophilicity is also improved, so that the adhesive residue on the skin surface can be prevented, and the absorption of sweat from the skin surface becomes good, and the skin adhesiveness is improved. It is effective in improving and reducing skin irritation.

As described above, the pressure-sensitive adhesive used in the present invention has excellent properties in a disease treatment tape preparation containing a basic drug having a free base structure, but when further improvement in cohesive force is desired, The crosslinking treatment may be carried out by copolymerization of a crosslinkable monomer, blending of various crosslinking agents, irradiation of various radiations and the like.

The drug used in the present invention is stably retained by the above-mentioned pressure-sensitive adhesive, is released to the skin surface, and is transdermally absorbed into the living body, and as a result, exerts an effect in the treatment and prevention of various diseases. .

The drug is not particularly limited as long as it is a basic drug having a free base structure, and also includes hydrochloride, sulfate, phosphate, tartrate, maleate, mesylate, fumarate, lactate, A basic drug having an acid salt structure such as an acetate salt or a hydrobromide salt may be used after being made free by a known means.

Specific examples of such basic drugs having a free base structure are shown below by classifying them from the viewpoint of pharmacological action.

Hypnotic / sedative: Flurazepam, etc.

Antipyretic, analgesic and anti-inflammatory drugs: tinoridine, benzydamine, perisoxal, lefetamine, tramadol, dimethothiazine, buprenorphine, butorphanol, etc.

Excitatory / stimulant: Methamphetamine, etc.

Antispasmodic: Meclizine, dl-isoprenaline, diphenidol, betahistine, etc.

Psychiatry and nerve agents: phenothiazines such as chlorpromazine, triflupromazine, levomepromazine, perazine, prochlorperazine, trifluoperazine, thioproperazine, thioridazine, fluphenazine, perphenazine and spiclorudine, and phenothiazines such as flupenthixol. Similar skeletal drugs, butyrophenone drugs such as floropipamide and moperone, diphenylmethane drugs such as hydroxyzine, carpipramine drugs such as carpipramine and clocapramine, imipramine, desipramine, trimipramine, clomipramine, amitriptyline, nortripraline, doslepine, melitracene, lofepramine Tricyclic antidepressants such as, tetracyclic antidepressants such as mianserin and maprotiline, MAO inhibitors such as saprazine, chlordiazepoki Benzodiazepines, such as de, other methylphenidate, such as pipradrol.

Skeletal muscle relaxants: prediol, eperisone, tolperisone, etc.

Antispasmodics: atropine, scopolamine, dicyclomine, diethylaminoethyl diphenylhydroxypropionate, pipetanate, piperidate, oxyphencyclimine, methixene, papaverine, etc.

Anti-Parkinson drugs: pepiliden, trihexphenidine, amantadine, pyroheptin, prophenamine, mazaticol, etc.

Antihistamines: diphenhydramine, carbinoxamine, chlorpheniramine, alimemazine, isothipendyl, triprolidine, clemizole, cyproheptadine, homochlorcyclidine, diphenylpyraline, iproheptin, dimethindene, clemastine, etc.

: Cardiotonic: Isopreterenol, dopamine, dobutamine, metallaminol, etilefrine, norphenephrine, etc.

: Antiarrhythmic drugs: procainamide, lidocaine, quinidine, prapanolol, alprenolol, bufetrol, bupranolol, oxprenol, indenolol, carteolol, befnolol, albutolol, bumolol, timolol, alotinolol, disopyramide, mexiletine, verapamil , Aplidine etc.

Antihypertensive agents: ecarazine, hydralazine, dimethylaminoethyl reserpine, dihydroergotoxin, guanfacine, clonidine, bunazosin, bunitrolol, prazosin, propranolol, labetalol, guanabenz, enalaprin, guanethidine, betanidine, penbutolol, etc.

: Vasoconstrictor: phenylephrine, methoxamine, dihydroergotamine, etc.

: Coronary vasodilators: etafenone, oxyfedrine,
Dilazeb, diltiazem, trimetazidine, verapamil, carbochromene, perenilamine, etc.

Peripheral vasodilators: isoxuprine, nicametate, nicotinic alcohol, bamethane, tolazoline, etc.

Other cardiovascular drugs: nicardipine, pyrithioxine,
Flunarizine, Meclofenoxate, Moxicilito,
Ifenprodil, bromincamine, bencyclamine,
Cinepagide, Chiapride, etc.

Respiratory agents: lobeline, levallorphan, dimephrine, doxapram, naloxone, etc.

Antitussive expectorants: codeine, dihydrocodeine, dextromethorphan, carbetapentane, benproperine,
Tipepidine, isoaminyl, dimemorphan, oxerazine, ebrazinone, clobutinol, clofedanol, hominoben, noscapine, L-methylcysteine,
Bromhexine, ambroxol, epinephrine, ephedrine, methylephedrine, isopreterenol, orciprenaline, terbutaline, salbutanol, trimethoquinol, chlorprenaline, methoxyphenamine, hexoprenaline, vitorterol, procatechol, tulobuterol, pirbuterol, fenoterol, formoterol. Terrol, clenbuterol, mabuterol, ketotifen, azelastine, etc.

Hormones: such as clomiphene.

Drugs for purulent diseases: Mafenide etc.

Analgesic, antipruritic, astringent, anti-inflammatory drug: Isotipendil etc.

Drugs for parasitic skin diseases: miconazole, econazole,
Iconazole, Sconazole, Oxyconazole, Croconazole, etc.

Vitamins: dicethiamine, shicothiamine, pyridoxine, etc.

Hemostatic agents: Adrenochrome guanylhydrazone etc.

Anticoagulant: Ticlopidine etc.

Antidote / addictive drug: Deferoxamine etc.

Diabetes drugs: Metformin, Buformin, etc.

Anti-neoplastic agents: nitrogen mustard-N-oxide, improsulfan, nimustine, ancitabine, vinblastine, vincristine, vindesine, daunorubicin, doxorubicin, tamoxifen, procarbazine, etc.

Narcotics: ethylmorphine, morphine, codeine, dihydrocodeine, cocaine, pethidine, fentanyl, etc.

In the present invention, one or more kinds of the above-mentioned drugs are contained in the pressure-sensitive adhesive to prepare the drug-containing pressure-sensitive adhesive layer. The amount of the drug to be blended may be a pharmacologically effective amount, but when an acrylic copolymer having the inactivated carboxyl group in the molecule is used as an adhesive, the above-mentioned free functional groups are added to these functional groups. Since a basic drug having a basic structure may be trapped, it is preferable to add more than the number of moles of functional groups in the pressure-sensitive adhesive. The compounding amount is an equimolar amount to 20-fold molar amount, preferably 1.1-fold molar amount to 10-fold molar amount of the number of moles of the functional group in the pressure-sensitive adhesive. By compounding in this way, the initial release of the drug is improved and the contained drug is continuously released over a long period of time.

Further, the disease treatment tape preparation of the present invention, in order to improve the transdermal absorbability of the drug, polyethylene glycol, lanolin, olive oil, silicone oil, urea, dimethyl sulfoxide, dimethylformamide, diisopropyl adipate, isopropyl myristate, An auxiliary substance such as a terpene resin may be blended in a range that does not impair the stability or release of the drug, for example, in the range of 1 to 30% by weight, preferably 5 to 15% by weight in the drug-containing pressure-sensitive adhesive layer.

<Effects of the Invention> As described above, the tape preparation for disease treatment of the present invention has a good transdermal absorbability because it uses a basic drug having a free base structure as a drug. Further, since a pressure-sensitive adhesive made of an acrylic copolymer having an inactivated carboxyl group in the molecule is used as the drug-containing pressure-sensitive adhesive, the sustained-release property of the drug is improved in addition to the above characteristics. In this case, by making the compounding amount of the drug more than the number of moles of the functional group in the pressure-sensitive adhesive, the initial release property of the drug is improved, the drug is continuously released for a long time, and various release patterns are designed. It becomes possible.

<Example> An example of the present invention will be shown below, and will be described more specifically. In the following, parts and% in the text mean parts by weight and% by weight.

Example 1 96 parts of acrylic acid isononyl ester and 4 parts of acrylic acid were polymerized in ethyl acetate using azobisisobutyronitrile as a polymerization initiator to obtain a pressure-sensitive adhesive solution.

Sodium hydroxide was added to the obtained adhesive solution to inactivate 90% of the carboxyl groups in the adhesive.

Timolol was added to the pressure-sensitive adhesive solution obtained by deactivating a part of the carboxyl groups obtained as described above (timolol content 20% / solid content), and this was dried on one side of a 12 μm-thick polyethylene terephthalate film. Has a thickness of 40μ
m to obtain a tape formulation for treating diseases of the present invention. The molar ratio between the total amount of carboxyl groups and the amount of timolol in the adhesive was 4.44 / 6.32.

Comparative Example A tape preparation was obtained in the same manner as in Example 1 except that timolol maleate was used as the drug.

Using the tape preparations obtained in Example 1 and Comparative Example, the daily stability of the drug, skin adhesion, skin irritation, and rabbit skin transfer amount were measured. The respective characteristics were measured by the following methods. The results are shown in Table 1 and FIG.

(Drug stability over time / drug residual ratio) Each tape preparation piece cut into a size of 5 × 4 cm ² was stored at 40 ° C., and the residual drug ratio to the content before storage was calculated. Quantitation was performed by high performance liquid chromatography.

(Amount Transferred to Rabbit Skin) Tape preparations obtained in Example 1 and Comparative Example (30 mm
φ) was attached to a rabbit whose hair was removed from the back (Japanese white native species), and the amount of drug remaining in the tape was quantified by high performance liquid chromatography at regular intervals to measure the amount transferred to the skin (3 samples). Average value).

(Skin Adhesion) A tape preparation piece cut into 3 cmφ was attached to the inside of a human upper arm, and the adhesion state after 24 hours was visually determined according to the following criteria (6 person average).

○: 90% or more of the applied area is adhered.

Δ: 50 to 90% of the applied area is adhered.

X: Less than 50% of the applied area is adhered.

(Skin irritation) A tape preparation piece cut into 3 cmφ was attached to a human chest for 2 hours, and 6 hours after peeling, the skin condition was visually evaluated according to the following criteria. The score is the average value of 6 people.

0 points: no reaction 0.5 points: slight erythema 1.0 points: clear erythema 2.0 points: erythema and papules or edema 3.0 points: erythema and edema and papules or small chicken pox 4.0 points: large chickenpox As is clear from Table 1 and FIG. 1 above, when a basic drug having a free base structure is used as a tape preparation, it is relatively excellent in release properties and has good stability, skin adhesiveness, and skin irritation. is there. Moreover, when an adhesive having a carboxyl group as a functional group is used, sustained release is exhibited. Furthermore, by making the amount of drug larger than the number of moles of the functional group in the pressure-sensitive adhesive, it becomes possible to have both initial release property and sustained release property.

[Brief description of the drawings]

FIG. 1 is a graph showing the amount of drug transfer from the tape preparations obtained in Example 1 and Comparative Example to rabbit skin.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshifumi Hosaka 1-2-1 Shimohozumi, Ibaraki City, Osaka Prefecture Seiko Tamura Examiner, Nitto Denko Corporation (56) References JP 62-29516 (JP, SHO 62-29516) A) JP 62-228008 (JP, A) JP 59-48416 (JP, A) JP 59-59613 (JP, A) JP 63-255219 (JP, A) JP 59 -42314 (JP, A) JP 59-184120 (JP, A) JP 59-184121 (JP, A) JP 59-184122 (JP, A)

Claims (2)

(57) [Claims] 1. A tape preparation comprising a flexible support and a drug-containing pressure-sensitive adhesive layer containing a basic drug having a free base structure in the pressure-sensitive adhesive, the pressure-sensitive adhesive having a carbon number. 4-
A copolymer obtained by inactivating a part or all of the carboxyl groups of a copolymer obtained from a monomer having a carboxyl group in the molecule with an alkyl acrylate ester having 12 alkyl groups in the molecule. A tape preparation for treating a disease characterized by being present. 2. The basic substance is an alkali metal hydroxide,
The tape preparation for disease treatment according to claim 1, which is at least one selected from hydroxides of alkaline earth metals and quaternary amines.