CA2209862A1 - Acylated cyclodextrin-containing pharmaceutical composition - Google Patents
Acylated cyclodextrin-containing pharmaceutical compositionInfo
- Publication number
- CA2209862A1 CA2209862A1 CA002209862A CA2209862A CA2209862A1 CA 2209862 A1 CA2209862 A1 CA 2209862A1 CA 002209862 A CA002209862 A CA 002209862A CA 2209862 A CA2209862 A CA 2209862A CA 2209862 A1 CA2209862 A1 CA 2209862A1
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- Canada
- Prior art keywords
- acylated
- drug
- cyclodextrin
- pharmaceutical composition
- per
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Abstract
A pharmaceutical composition for trans-mucosal or transdermal administration wherein a per-C 2 1 8 acylated cyclodextrin is used as a drug reservoir or carrier. The composition can be used safely and exhibits excellent drug release behavior.
Description
Acylated Cyclodextrin-Containing Pharmaceuti-cal Composition BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to the use of per-acylated cyclodextrin in a pharmaceutical composition, and more specifically, relates to a pharmaceutical composition wherein a per-C 2 -1 8 acylated cyclodextrin is 10 used as a drug carrier, and further to a process for preparing such a composition having a specified form.
1. Field of the Invention This invention relates to the use of per-acylated cyclodextrin in a pharmaceutical composition, and more specifically, relates to a pharmaceutical composition wherein a per-C 2 -1 8 acylated cyclodextrin is 10 used as a drug carrier, and further to a process for preparing such a composition having a specified form.
2. Description of Prior Arts Cyclodextrin (hereinafter, referred to as CyD) is an oligosaccharide wherein glucose residues are cyclically bound through ~-1,4 bond. Those which are each composed of 6, 7 or 8 glucose residues and each of which is called ~,~ or ~-CyD respectively have been put to practical use. These CyDs have a high clathrating ability on certain chemical substances, and are uti-lized, in the field of pharmaceuticals, food and cosme-tics, for various uses such as stabilization, retention of volatile substances and solubilization of substances which are sparingly soluble or insoluble in water.
Further, for the purpose of utilizing such physicochemical characteristics and clathrating ability of CyD as a multifunctional drug carrier, etc., various CyD derivatives are provided. For example, partially acylated cyclodextrin for solubilizers, preparation 30 aids, stabilizing agents, degreasing agents, solvent-substitutes, and further, coating materials, fixing aids, phase transfer catalysts and masking agents on the sense of taste and the sense of smell are described in Japanese Laid-Open (Kokai) Patent Publication No.
300501/1995.
Furthermore, there can be taken, as noteworthy compounds, heptakis (2,3,6-tri-0-acetyl)-~-cyclodextrin and octakis (2,3,6-tri-0-acetyl)-~-cyclodextrin for use in combination with an water-soluble drug described in K. Uekawa et al., J. Controlled Release, 31 (1994), 173-180, and peracylated ~-cyclodextrins described in J.
Pharm. Pharmacol. 1994, 46: 714-717; Chem. Pharm. Bull.
43 (1995), 130-136 and Pharmaceutical Science 1995, 1:
517-520. As for these peracylated ~-cyclodextrins, there have been disclosed those having acyl groups 10 having 2 to 12 carbon atoms, among which some that have a certain chain length can be used in combination with a water-soluble drug such as morsidomine or salbutamol to form a preparation which is interesting in that, when orally administered to experimental animals, it allows 15 the release rate of the drug to be controlled. In the above J. Pharm. Pharmacol. 1994, 46: 714-717, it is shown that particularly, perbutanoyl (C 4) -~-CyD remark-ably retards the drug release rate, compared with other aclated ~-CyDs. It has been suggested that this action is caused by the appropriate adhesion to mucosa and hydrophobicity of perbutanoyl-~-CyD.
On the other hand, attention has been drawn in recent years to the development of pharmaceuticals for the trans-mucosal or transdermal administration of drugs 25 which have systemic or topical actions toward various diseases, with a view to decreasing compliance of pa-tients. However, since it is difficult to control the release of drugs from pharmaceuticals, it has been necessary to use various additives or, in the case of solid drugs, to employ a solvent to dissolve the solid drugs with. Further, there is a case where it is neces-sary to select additives to be compounded for the pur-pose of controlling the release of drug or promoting its absorption or solvents for dissolving the drug. These 35 materials are, however, generally irritative to skin or cutis, thus causing problems that long-term use is difficult. Particularly, many of absorption enhancers for drugs have generally a high solubility in lipid, and it is said that almost all of the above absorption enhancers interact with the adhesives in transdermal absorption compositions, with the result that adhesion or adhesive force between the pharmaceuticals and the cutis is adversely influenced (Development of Pharmaceu-ticals, 12, page 374, Chapter 3 Pharmaceutical Materials Expectable in New Functions, published by Hirokawa 10 Shoten in 1988).
In order to overcome these problems, it has been proposed to place a drug reservoir and an absorp-tion enhancer reservoir separately, or there has been proposed a peripheral-type pharmaceuticals for trans-dermal absorption wherein the adhesives are placed onlyat the periphery, as in tranzone, and, thus, certain results have been attained.
However, there are still needs for a composi-tion for trans-mucosal or transdermal administration 20 which is easy to prepare, excellent in drug releas-ability from the pharmaceutical composition and excel-lent in absorptivity in a living body of the released drug. Thus, the object of the invention lies in provid-ing a pharmaceutical composition satisfying the above needs.
SUMMARY OF THE INVENTION
In order to solve the above problems, the present inventors have studied the trans-mucosal and 30 transdermal administration of various compositions. As a result, they have found that certain peracylated cyclodextrins are excellent not only in the adhesion to mucosa, but in the releasability of the drugs from compositions prepared therefrom, and moreover, heighten 35 the absorptivity of the released drugs into living bodies.
Thus, according to the invention, there is provided a pharmaceutical composition for the trans-mucosal or transderma ! administration comprising a per-C2 _ 1 8 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
Another object of the present invention is to provide a pharmaceutical composition for the trans-mucosal or transdermal administration comprising the per-C2 _ 1 8 acylated cyclodextrin and the drug, said 10 composition being in the form of a sheet or fiIm.
Yet another object of the present invention is to provide a method for the trans-mucosal or transdermal administration of a drug which comprises applying said composition to the mucosa or cutis of an individual who needs to be treated with the drug.
Still another object of the present invention is to provide a process for preparing a sheet-like or filmy pharmaceutical composition using the acylated cyclodextrin.
Although not bound by the theory, it is sur-mised that, according to the composition of the inven-tion, the acyl groups densely standing in a row on the CyD molecule heighten the adhesion to mucosa and cutis, and further that, if the composition is molded into a sheet-like or fiImy form, the acyl groups form an envi-ronment rich in airtightness, prevent transpiration, etc. of water from the applied surface, and thereby heighten the cutis-permeability of drugs. Further, the per-C2 ~ 8 acylated CyD used in the invention is very low in irritativeness on mucosa and cutis. Besides, the per-C2 ~ 8 acylated CyD used in the invention takes a solid, liquid or wax-like form, and it is guessed that, when combined with a drug, said compound will act as a solubilizing agent (or solvent), adsorbent or clathrat-ing agent.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph which shows comparison on detaching force between trivaleryl-~-cyclodextrin and the various hydrophilic macromolecules, using a probe tack tester.
Fig. 2 is a graph which shows comparison on detaching force among the cohesive compositions, which contain the absorption enhancer and the isosorbide dinitrate preparation on the market, using a probe tack 10 tester.
Fig. 3 is a graph which shows the drug release with time lapse from the adhesive compositions having different diameters and the isosorbide dinitrate prepa-ration on the market, at 34~C, using the drug release-15 measuring apparatus. The black triangular symbol shows Frandle Tape S, the white triangular symbol ISDN/TV-~-CyD (diameter: 3 cm), the black round symbol ISDN/TV-~-CyD (diameter: 2 cm), and the white round symbol ISDN/TV-~-CyD (diameter: 1 cm).
Fig. 4 is a graph which shows the isosorbide dinitrate concentration in the plasma with time lapse after the isosorbide nitrate/trivaleryl-~-cyclodextrin adhesive composition was administered onto the rat abdominal part. The black round symbol shows ISDN/TV-~-CyD/OA (molar ratio: 1/1/0.2) and the white round symbol shows ISDN/TV-~-CyD (molar ratio: 2/1).
Fig. 5 is a schematic drawing of the apparatus for conducting the automatic dissolution test of the drug from the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
The term per-C2 ~ 8 acylated in the invention means that all the hydroxyl groups in the cyclodextrin molecule are acylated. So long as the object of the invention is achieved, the term also includes the case where 90 % or more in average of all the hydroxyl groups in the cyclodextrin molecule (e.g., 21 in ~-CyD) are acylated. The acylation rate is preferably 95 % or more, but 100 % (i.e., all the hydroxyl groups in CyD
are completely acylated) is most desirable.
Further, the cyclodextrin in the invention includes not only the above-mentioned a-CyD, ~-CyD and ~-CyD, but so-called branched CyDs wherein one or plural glucose residues are added thereto, but ~-CyD is partic-ularly preferred. Thus, although hereinafter, the invention is described citing ~-CyD for making the description concise, it should be understood that other CyDs can be treated in the same manner and have the similar actions. When the above CyD wherein 100 % of the hydroxyl groups are acylated is more specifically expressed, it corresponds to heptakis (2,3,6-tri-0-acyl)-~-cyclodextrin.
Specific examples of the acyl groups which are referred to in the C 2 - t 8 acylation include acetyl, propanoyl, butanoyl. pentanoyl (or valeryl), hexanoyl (or caproyl), heptanoyl (or enanthyl), octanoyl (or capryloyl), dodecanoyl (or lauroyl), tetradecanoyl (or myristoyl), octadecanoyl (or stearoyl) groups, etc., and acyl groups derived from branched chain fatty acids corresponding thereto, but acyl groups derived from straight-chain fatty acids are preferably used. These acyl groups can be the same or different, but conve-nience on preparation being taken into account, it is preferred that all the acy groups are the same.
Further, if the acylated CyD used in the invention has the same acyl group, ones having 4 to 8 carbon atoms are preferred, and ones having 4 to 6 carbon atoms are particularly preferred. For example, per-C5 acylated ~-CyD has, as such, fiIm formability, and per-C4 acylated ~-CyD or per-C6 acylated ~-CyD can also be molded into fiIm, if needed by adding a fiIm forming-high molecular compound or the like, and the fiIm can conveniently be used as a pharmaceutical compo-sition for trans-mucosal or transdermal administration according to the invention.
Thus, according to the invention, the acylated CyD can readily be molded, as the form of the composi-tion, into a filmy form and a sheet-like form. Although its details are made clear later, there is a case where-in, as to the composition molded into the form of a sheet or fiIm, the release patterns of the drug somewhat 10 differ between the side of the casting surface and the side of the opposite surface, and it is also possible to choose the surface to be applied to the mucosa or cutis, in accordance with the purpose of the drug used.
As to the composition of the invention molded into a fiImy or sheet-like form as stated above, its affinity to the surface to be applied can be adjusted by treating the surface by a suitable method to cause partial deacylation. As this treating method, there can be mentioned alkali treatment or treatment with a suit-able deacylating enzyme. The thus obtained partiallydeacylated composition of the invention is preferred especially in the point that if it is administered to a mucosa under an aqueous environment, for example the oral mucosa, the retentivity of the composition on the 25 mucosa is improved. Thus, a composition wherein partial deacylation is made by surface treatment of the above composition of the invention is also provided according to the invention.
As drugs to be incorporated in the composition 30 according to the invention, any drugs including water-soluble and water-sparingly soluble ones can be used so long as they are in line with the obiect of the inven-tion, but from the standpoint that they are trans-muco-sally or transdermally administered, there can, for example, be mentioned nonsteroidal antirheumatic agents, steroids, cardiac glycosides, benzodiazepine deriva-tives, benzimidazole derivatives, piperidine deriva-tives, piperazine derivatives, imidazole derivatives and triazole derivatives. Althsugh not limited thereto, as benzimidazole derivatives, there can be mentioned thia-bendazole, fuberidazole, oxibendazole, parbendazole,cambendazole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and astemizole.
Further, as suitable piperidine derivatives, there can be mentioned bruspirilen, bimotide, penfluridol, loper-10 amide, ketanserin, levocabastine, cisapride, altanserinand ritanserin. Further, as suitable piperazine deriva-tives, there can be mentioned lidoflazine, flunarzine, mianserin, oxatomide, miofurazine and cinnarizine.
Further, as suitablé imidazole deriva~ives, ~here can be 15 mentioned metronidazole, ornidazole, ipronidazole, tindazole, isoconazole, nimorazole. primamide, methi-amide, metomidate, enilconazole, etomidate, econazole, clotrima~ole, garnidazole, cimetidine, docodazole, sulconazole, parconazole, orconazole, butoconazole, 2G triadimin~l, Ti~on~2~1e, parconazole, fluotrimazole, ketoconazole, oxyconazole, rombazole, bifonazole, oxci-metidine, fenti~onazole an~ tabrazole. Fur~her, as suitable triazole derivatives, there can be mentioned birazole, itraconazole and terconazole. Further, a nitrous acid derivatives such as, isosorbide dinitrate or nitroglycerin can al~o preferably be incorporated in the composition of the invention.
In addition to the above drugs, this invention --covers also the following drugs, which are classified 30 according to their efficacy:
analgesic and anti-inflammatory drugs such as acetylsalicylic acid, sodium diclofenac, ibu-profen, i~dometh~cin, ketoprofen, sodium meclofenamate, mefenamic acid, sodium naproxen, paracet3mol. piroxicam and sodium tolmetin;
anti-arrhythmic drugs such as procainamide HCI, qunidine sulphate and verapamil HCI;
antibacterial agents such as amoxicillin, ampicillin, benzathine penicillin, benzyl-peniciilin, cefaclor, cefadroxil, cephalexin, chloramphenicol, ciprofloxacin, clavulanic acid, clindamycin HCI, doxycycline HCI, erythromycin, sodium flucloxacillin, kanamycin sulphate, lincomycin HCI, minocycline HCI, sodium nafcillin, nalidixic acid, neomycin, norfloxacin, ofloxacin, oxacillin and potas-sium phenoxymethyl-penicillin;
anti-coagulants such as warfarin;
antidepressants such as amitriptyline HCI.
amoxapine, butriptyline HCI, clomipramine HCI, desipramine H-CI, dothiepin HCI, doxepin HCI, fluoxetine, gepirone, imipramine, lithium carbonate, mianserin HCI, milnacipran, nortriptyline HCI and paroxetine HCI;
anti-diabetic drugs such as glibenclamide;
antifungal agents such as amphotericin, clotrimazole, econazole, fluconazole, flucy-tosine, griseofulvin, itraconazole, ketocona-zole, miconazole nitrate and nystatin;
antihistamines such as astemizole, cinnari-zine, cyproheptadine HCI, flunarizine, oxatomide~ promethazine and terfenadine;
anti-hypertensive drugs such as captopril, enalapril, ketanserin, lisinopril, minoxidil, prazosin HCI, ramipril and reserpine;
anti-muscarinic agents such as atropine sul-phate and hyoscine;
antivirals such as acyclovir, AZT, ddC, ddl, ganciclovir, loviride, tivirapine, 3TC, dela-virdine, indinavir, nelfinavir, ritonavir and saquinavir;
sedating agents such as alprazolam, buspirone HCI, chlordiazepoxide HCI, chlorpromazine, clozapine, diazepam, flupenthixol HCI, fluphe-nazine, flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine, risperidone, selfotel, seroquel, sulpiride, temazepam, thiothixene, triazolam, trifluperidol and ziprasidone;
anti-stroke agents such as lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil and remacemide;
anti-migraine drugs such as alniditan and sumatriptan;
beta-adrenoreptor blocking agents such as atenolol, carvedilol, metoprolol, nebivolol and propranolol;
cardiac inotropic agents such as digitoxin, digoxin and miIrinone;
corticosteroids such as beclomethansone dipro-pionate, betamethasone, dexamethasone, hydro-cortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
disinfectants such as chlorhexidine;
diuretics such as acetazolamide, frusemide, hydrochlorothiazide and isosorbide;
anti-Parkinsonian drugs such as bromocryptine mesylate, levodopa and selegiline HCI;
enzymes or essential oils such as anethole, anise oil, caraway, cardamom, cassia oil, cinelole, cinnamon oil, clove oil, coriander oil, dementholised mint oil, dill oil, euca-lyptus oil, eugenol, ginger, lemon oil, mus-tard oil, neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol and thyme;
gastro-intestinal agents such as cimetidine, cisapride, clebopride, diphenoxylate HCI, domperidone, famotidine, lansoprazole, loper-amide HCI, loperamide oxide, mesalazine, metoclopramide HCI, mosapride, olsalazine, omeprazole, ranitidine, rabeprazole, ridogrel and sulphasalazine;
haemostatics such as aminocaproic acid;
lipid regulating agents such as lovastatin, pravastatin, probucol and simvastatin;
local anaesthetics such as benzocaine and llgnocalne;
opioid analgesics such as buprenorphine HCI, codeine, dextromoramide and dihydrocodeine;
parasympathomimetics such as galanthamine, neostigmine, physostymine, tacrine, donepezil, ENA 713 (exelon) and xanomeline; and vasodilators such as amlodipine, buflomedil, amyl nitrite, diItiazem, dipyridamole, gly-ceryl trinitrate, isosorbide dinitrate, lido-flazine, molsidomine, nicardipine, nifedipine, oxpentifylline and pentaerythritol tetra-nitrate.
In the composition according to the invention, the compounding ratio between the peracylated CyD and the drug can be any ratio so long as it meets the ob-ject, but from the standpoint to control the releas-ability of the drug from the composition, it is possible 20 to choose, as the ratio of the peracylated CyD to the drug, 1:4 to 4:1, preferably 1:2 to 2:1, as molar ratio.
Further, the composition of the invention can, if necessary, contain other pharmaceutically acceptable auxiliaries or additives in such a range that the object 25 of the invention is not adversely influenced. Examples of such auxiliaries or additives include absorption enhancers or skin permeability enhancers for drugs, physical property improvers, stabilizers, etc.
Examples of absorption enhancers include 1-dodecylhexahydro-2H-azepin-2-one, fatty acids such as oleic acid, pyrrolidone derivatives such as N-methyl-pyrrolidone, thioglycolates such as potassium thiogly-colate or calcium thioglycolate, fatty acid alcohol esters such as diisopropyl adipate, enamines, salicylic 35 acid derivatives, sodium caprate, menthol, and the like.
The absorption propoters may be added to the composition in about up to 0.5%, preferably in about 1% to about 10%, by weight per total weight of the composition.
Examples of physical property improvers include surfac-tants such as polyoxyethylene fatty acid esters, poly-oxyethylene polyoxypropylene block copolymers and fattyacid glycerol esters, thickeners such as xanthane gum, carboxyvinyl polymers, sodium carboxymethylcellulose, polyvinyl pyrrolidone, methylcellulose, hydroxypropy cellulose and propylcellulose, and colorants such as 10 food dyes and iron oxides. Examples of stabilizers include antioxidants such as ascorbic acid, ascorbic palmitate, thioglycerol, dl-~-tocophelol, butylhydroxy-toluene, butylhydroxyanisole and propyl gallate, and preservatives such as benzalkonium chloride, sorbic acid and paraoxybenzoic acid esters such as methyl paraben, ethylparaben and benzylalcohol.
The composition according to the invention can be produced by a formulation method known per se, but can preferably be produced as follows.
Peracylated ~-CyD and a drug are dissolved in an organic solvent incompatible with water, this solu-tion is added dropwise onto a water surface and devel-oped, and the solvent is volatilized to give a fiImy composition having adhesion. In this connection, as conditions for removing the organic solvent, there can be chosen a condition fit for the drug such as ordinary pressure and ordinary temperature, heating under ordi-nary pressure or heating under reduced pressure or the like. Further, it is possible to obtain a fiImy compo-sition having adhesion by dissolving peracylated ~-CyD
and a drug in an organic solvent, adding dropwise the solution onto aluminum foil, polyethylene terephthalate film, polystyrene fiIm or the like, developing it, and volatilizing the solvent in the same manner as mentioned above. If such a process is used and pervaleryl (C 5) -~-CyD is used as the peracylated ~-CyD, a transparent filmy composition can be obtained without using other additives.
It is not disclosed in prior art literatures that such a fiImy composition can be obtained, and herein, there is provided, as another embodiment of the invention, a process for preparing a sheet-like or filmy pharmaceutical composition for trans-mucosal or trans-dermal administration which contains a step of casting a solution or suspension containing a per-C 2 -1 8 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
Further, it is possible to obtain a powdery or granular composition by dissolving peracylated ~-CyD and a drug in an organic solvent, and distilling off the solvent by a rotary evaporator or the like. It is also possible to obtain a composition by heat melting per-acylated ~-CyD and a drug, cooling the melt, and if necessary, grinding the cooled matter.
Certain peracylated CyDs can be produced 20 according to the process described in the above Chem.
Pharm. Bull., 43 (1995), 130-136, and the acylated derivatives of CyDs used in the invention canr for example, be produced by dissolving ~-CyD in anhydrous pyridine, adding an organic acid corresponding to the length of acyl group such as acetic anhydride or valeric anhydride at room temperature and under an anhydrous condition, and stirring with heating to around 80~C.
After confirmation of the completion of the reaction with thin layer chromatography, the reaction solution is 30 added to ice-water, the precipitate deposited and the oily matter were extracted with a solvent such as chlo-roform, the obtained extraction product is concentrated over anhydrous magnesium sulfate, and the concentrate is subjected to separation and purification by silica gel chromatography. Further, the purified product is dis-solved in chloroform, the solution is sufficiently CA 02209862 l997-07-04 washed with an aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate, the solvent is distilled off, and further, the residue is recrystal-lized from methanol to give purified acylated ~-CyD.
In the composition according to the invention, the peracylated cyclodextrin and the drug exist in such a state that they are in a molecular state and can interact (e.g., the drug is clathrated in the CyD mole-cule), and the outside of the cyclodextrin molecule 10 exhibits hydrophobicity and is good in contact with the skin or mucous membrane, and moreover, gives almost na irritation on them. Therefore, the drug is directly released from the composition to the cutis or mucosa.
Namely, the movement of the drug molecule and the perme-ation thereof into the mucosa are possible without theaid of water or a solvent or the like.
Thus, according to the invention, there is provided a pharmaceutical composition for trans-mucosal or transdermal administration which is safe and excel-lent in the release behavior of the drug and skin perme-ability.
Hereinafter, examples are mentioned, aiming to describe the invention more specifically.
ExamPle (comParison) 1 Adhesive characteristic of PervalerYI-~-cYclodextrin Pervaleryl-~-cyclodextrin (TV-~-CyD)-contain-ing absolute ethanol solution (concentration: 150 mg/ml) was added dropwise onto a backing membrane (poly-30 ethylene terephthalate film) using a microsyringe, andallowed to stand at 25~C for 24 hours to evaporate ethanol, whereby fiIms of TV-~-CyD having adhesion were obtained.
The detaching force on the fiIms of TV-~-CyD
and on the fiIms derived from various hydrophilic macro-molecules (hydroxypropylcellulose (HPC), hydroxypropyl-CA 02209862 l997-07-04 methylcellulose (HPMC) and polyhydroxyethyl methacrylate (PHEMA)) was measured using a probe tack tester (pro-duced by Rigaku Kogyo Co.). The results are shown in Fig. 1. The fiIms of hydrophilic macromolecules were prepared as described with respect to TV-~-CyD. The drawing shows that TV-~-CyD is the strongest in adhe-sion.
ExamDle (comParison) 2 Cutis irritativeness of ~er-TV-~-CvD
There was stuck 150 mg of TV-~-CyD, in the shape of a circle with a diameter of 20 cm, on the back of female hairless mice at the age of around 7 weeks (weight: 50-60 g), and 16 hours later, the cutis was extirpated. The extirpated cutis was fixed with 20 %
neutrally-buffered formalin solution and embedded in paraffin according to a usual manner, and tissue sec-tions were prepared using a microtome. These sections were double stained with haematoxylin and Eosine, and observed by a light microscope. Untreated cutis was 20 used as control. Moreover, a commercially available adhesive tape for patch test was applied on the same mice under the same condition, and, thereafter. the cutis tissue of the applied portion was extirpated for comparison. In the case of TV-~-CyD, there was observed peeling of corneum in the same degree as in the case of the commercially available adhesive tape. Other sites (control), however, showed no abnormality such as in-flammatory cellular infiItration.
Examples (invention) 3 to 6 30 Adhesive characteristic of adhesive comDositions and adhesive comPositions containin~ an absor~tion enhancer Isosorbide dinitrate (ISDN) (3.4-6.7 mg) was dissolved in a TV-~-CyD-containing ethanol solution (concentration: 150 mg/ml), so as to give the following 35 molar ratios, respectively, and each solution was added dropwise onto a backing membrane (polyethylene tere-phthalate film) using a microsyringe, and allowed to stand at 25~C for 24 hours to evaporate ethanol, whereby an ISDN/TV-~-CyD composition having adhesion was ob-tained.
Isosorbide dinitrate (ISDN) (3.4-6.7 mg) was dissolved in a trivaleryl-~-cyclodextrin (TV-~-CyD)-cont aining ethanol solution (concentration: 150 mg/ml), respectively, and oleic acid (OA) was added (concentra-tion: 4 w/v%). Each of the resultant solutions was 10 added dropwise onto a backing membrane (polyethylene terephthalate film) using a microsyringe, and allowed to stand at 25~C for 24 hours to evaporate ethanol, whereby an ISDN/TV-~-CyD/OA containing the absorption enhancer and having adhesion was obtained.
The adhesion of ISDN/TV-~-CyD (molar ratio 1/1: Example 3; 2/1: Example 5), ISDN/TV-~-CyD/OA
(molar ratio 1/1/0.2: Example 4; 2/1/0.2: Example 6), and a commercially available isosorbide dinitrate prepa-ration (Frandle Tape S, comparison) was measured using a 20 probe tack tester (produced by Rigaku Kogyo Co.), and the results are shown in Fig. 2. As is seen apparently in the above, the present adhesive composition exhibits good adhesion even if it contains the absorption enhan-cer.
ExamPles (invention) 7 to 10 Dru~ release from adhesive comoositions ISDN/TV-~-CyDs having different diameters (diameter: 1 cm, 2 cm and 3 cm) were prepared in the same manner as in Examples 3 to 6. Drug release was 30 measured according to the Second Method (Paddle Method) of Dissolution Test in the Japan Pharmacopeia Xll using an automatic dissolution test apparatus (see Fig.5), in the following manner. ISDN/TV-~-CyD was fixed on an aluminum plate and put in a jacket beaker (inside diame-35 ter 5 cm, content volume 200 ml) through which circulat-ing water of 34~C was passed, and, then, 50 ml of deaerated eluent was introduced into said jacket beaker.
The I SDN concentration was measured by a circulating UV
detector (produced by SHI MADZU CORPORAT I ON) . For com-parison, measurement was conducted on Frandle Tape S in the same manner. The results are shown in Fig. 3. The I SDN/TV-~-CyD having a diameter of 3 cm exhibited a release equivalent to Frandle Tape S, and, thus, a good drug release was shown.
Examoles (invention) 11 to 12 10 Transdermal administration from cohesive comDosition I SDN/TV-~-CyD (molar ratio 2/1: Example 11) and I SDN/TV-~-CyD/OA (molar ratio 1/1/0.2: Example 12) were prepared in the same manner as in Examples 3 to 6.
Wister male rats (weight: about 240 g) whose hair of 15 the abdominal part had been removed under anesthetiza-tion were fixed on their backs, and the above I SDN/TV-~-CyD or I SDN/TV-~-CyD/OA was stuck on the unwounded part of each rat. Blood (0.6 ml) was taken with the lapse of time from the cervical vein using a syringe treated with heparin. To 0.2 ml of plasma from each of the obtained bloods, there was added 0.5 ml of 0.5 M phosphate buf-fer, and extraction was conducted with 6 ml of chloro-form. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in mobile phase of 25 methanol/water (1:4 v/v), and the ISDN concentration was measured by HPLC. The changes with time lapse of the I SDN concentration in the plasma after the administra-tion to the abdominal parts of the rats are shown in Fig. 4. The values in the results are expressed as the 30 mean + SE (n = 3).
Each of the fiIms maintained an ISDN concen-tration in the plasma of 40 ng/ml or more, which is an effective concentrat;on, for 12 hours or more.
.
Conditions of the above High-performance Liquid Chroma-tography (HPLC) were as follows:
Pump: 655 A-11 Type HPLC made by Hitachi Seisakusho K.K.
UV Detector: 655 A Type Wave Variable UV
Monitor made by Hitachi Seisakusho K.K.
Integrator: D-2500 Type Chromato-lntegrator made by Hitachi Seisakusho K.K.
Column: Shiseido Capsule PAK C8 SG120 o A (5 ~m, 4.6 mm ~ x 300 mm) Mobile Phase: methanol/water (1:4 v/v) Flow Rate: 1.0 ml/min.
Measured Wave Length: 210 nm Example (invention) 13 Pharmaceutical com~osition a~licable to oral mucous membrane containin~ triamcinolone White crystals (50 g) of perbutanoyl-~-cyclo-dextrin (TB-~-CyD) were dissolved in ethanol (200 ml), 20 and, then, triamcinolone (12.6 g) was added. After stirring, drying with heating was conducted under re-duced pressure at 60~C for 3 hours. To the resultant powder (62 g), there were added lactose (120 g), corn starch (40 g), microcrystalline cellulose (Avicel~
PH102: 18 g), hydroxypropylmethylcellulose [HPMC
(TC-5.S: 6 g)] and magnesium stearate (0.04 g), and the mixture was uniformly mixed and tableted to give tablets administrable to oral mucosa.
A tablet contained the following components:
5 mg of triamcinolone 20 mg of TB-~-CyD
17 mg of lactose 7.5 mg of Avicel~ PH102 2.5 mg of HPMC (TC-5.S), and trace amount of magnesium stearate Total: 102 mg The obtained tablets were tested for their characteristics (contents, fragileness and weight devia-tion) according to Preparation General Rules of The Japan Pharmacopeia Xll, and as a result they are found to be fit for all the test items. They were good in adhesion to the cheek, and adhesion was recognized to be durable. Further, there was no irritation to mucosa at the time of application.
Further, for the purpose of utilizing such physicochemical characteristics and clathrating ability of CyD as a multifunctional drug carrier, etc., various CyD derivatives are provided. For example, partially acylated cyclodextrin for solubilizers, preparation 30 aids, stabilizing agents, degreasing agents, solvent-substitutes, and further, coating materials, fixing aids, phase transfer catalysts and masking agents on the sense of taste and the sense of smell are described in Japanese Laid-Open (Kokai) Patent Publication No.
300501/1995.
Furthermore, there can be taken, as noteworthy compounds, heptakis (2,3,6-tri-0-acetyl)-~-cyclodextrin and octakis (2,3,6-tri-0-acetyl)-~-cyclodextrin for use in combination with an water-soluble drug described in K. Uekawa et al., J. Controlled Release, 31 (1994), 173-180, and peracylated ~-cyclodextrins described in J.
Pharm. Pharmacol. 1994, 46: 714-717; Chem. Pharm. Bull.
43 (1995), 130-136 and Pharmaceutical Science 1995, 1:
517-520. As for these peracylated ~-cyclodextrins, there have been disclosed those having acyl groups 10 having 2 to 12 carbon atoms, among which some that have a certain chain length can be used in combination with a water-soluble drug such as morsidomine or salbutamol to form a preparation which is interesting in that, when orally administered to experimental animals, it allows 15 the release rate of the drug to be controlled. In the above J. Pharm. Pharmacol. 1994, 46: 714-717, it is shown that particularly, perbutanoyl (C 4) -~-CyD remark-ably retards the drug release rate, compared with other aclated ~-CyDs. It has been suggested that this action is caused by the appropriate adhesion to mucosa and hydrophobicity of perbutanoyl-~-CyD.
On the other hand, attention has been drawn in recent years to the development of pharmaceuticals for the trans-mucosal or transdermal administration of drugs 25 which have systemic or topical actions toward various diseases, with a view to decreasing compliance of pa-tients. However, since it is difficult to control the release of drugs from pharmaceuticals, it has been necessary to use various additives or, in the case of solid drugs, to employ a solvent to dissolve the solid drugs with. Further, there is a case where it is neces-sary to select additives to be compounded for the pur-pose of controlling the release of drug or promoting its absorption or solvents for dissolving the drug. These 35 materials are, however, generally irritative to skin or cutis, thus causing problems that long-term use is difficult. Particularly, many of absorption enhancers for drugs have generally a high solubility in lipid, and it is said that almost all of the above absorption enhancers interact with the adhesives in transdermal absorption compositions, with the result that adhesion or adhesive force between the pharmaceuticals and the cutis is adversely influenced (Development of Pharmaceu-ticals, 12, page 374, Chapter 3 Pharmaceutical Materials Expectable in New Functions, published by Hirokawa 10 Shoten in 1988).
In order to overcome these problems, it has been proposed to place a drug reservoir and an absorp-tion enhancer reservoir separately, or there has been proposed a peripheral-type pharmaceuticals for trans-dermal absorption wherein the adhesives are placed onlyat the periphery, as in tranzone, and, thus, certain results have been attained.
However, there are still needs for a composi-tion for trans-mucosal or transdermal administration 20 which is easy to prepare, excellent in drug releas-ability from the pharmaceutical composition and excel-lent in absorptivity in a living body of the released drug. Thus, the object of the invention lies in provid-ing a pharmaceutical composition satisfying the above needs.
SUMMARY OF THE INVENTION
In order to solve the above problems, the present inventors have studied the trans-mucosal and 30 transdermal administration of various compositions. As a result, they have found that certain peracylated cyclodextrins are excellent not only in the adhesion to mucosa, but in the releasability of the drugs from compositions prepared therefrom, and moreover, heighten 35 the absorptivity of the released drugs into living bodies.
Thus, according to the invention, there is provided a pharmaceutical composition for the trans-mucosal or transderma ! administration comprising a per-C2 _ 1 8 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
Another object of the present invention is to provide a pharmaceutical composition for the trans-mucosal or transdermal administration comprising the per-C2 _ 1 8 acylated cyclodextrin and the drug, said 10 composition being in the form of a sheet or fiIm.
Yet another object of the present invention is to provide a method for the trans-mucosal or transdermal administration of a drug which comprises applying said composition to the mucosa or cutis of an individual who needs to be treated with the drug.
Still another object of the present invention is to provide a process for preparing a sheet-like or filmy pharmaceutical composition using the acylated cyclodextrin.
Although not bound by the theory, it is sur-mised that, according to the composition of the inven-tion, the acyl groups densely standing in a row on the CyD molecule heighten the adhesion to mucosa and cutis, and further that, if the composition is molded into a sheet-like or fiImy form, the acyl groups form an envi-ronment rich in airtightness, prevent transpiration, etc. of water from the applied surface, and thereby heighten the cutis-permeability of drugs. Further, the per-C2 ~ 8 acylated CyD used in the invention is very low in irritativeness on mucosa and cutis. Besides, the per-C2 ~ 8 acylated CyD used in the invention takes a solid, liquid or wax-like form, and it is guessed that, when combined with a drug, said compound will act as a solubilizing agent (or solvent), adsorbent or clathrat-ing agent.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph which shows comparison on detaching force between trivaleryl-~-cyclodextrin and the various hydrophilic macromolecules, using a probe tack tester.
Fig. 2 is a graph which shows comparison on detaching force among the cohesive compositions, which contain the absorption enhancer and the isosorbide dinitrate preparation on the market, using a probe tack 10 tester.
Fig. 3 is a graph which shows the drug release with time lapse from the adhesive compositions having different diameters and the isosorbide dinitrate prepa-ration on the market, at 34~C, using the drug release-15 measuring apparatus. The black triangular symbol shows Frandle Tape S, the white triangular symbol ISDN/TV-~-CyD (diameter: 3 cm), the black round symbol ISDN/TV-~-CyD (diameter: 2 cm), and the white round symbol ISDN/TV-~-CyD (diameter: 1 cm).
Fig. 4 is a graph which shows the isosorbide dinitrate concentration in the plasma with time lapse after the isosorbide nitrate/trivaleryl-~-cyclodextrin adhesive composition was administered onto the rat abdominal part. The black round symbol shows ISDN/TV-~-CyD/OA (molar ratio: 1/1/0.2) and the white round symbol shows ISDN/TV-~-CyD (molar ratio: 2/1).
Fig. 5 is a schematic drawing of the apparatus for conducting the automatic dissolution test of the drug from the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
The term per-C2 ~ 8 acylated in the invention means that all the hydroxyl groups in the cyclodextrin molecule are acylated. So long as the object of the invention is achieved, the term also includes the case where 90 % or more in average of all the hydroxyl groups in the cyclodextrin molecule (e.g., 21 in ~-CyD) are acylated. The acylation rate is preferably 95 % or more, but 100 % (i.e., all the hydroxyl groups in CyD
are completely acylated) is most desirable.
Further, the cyclodextrin in the invention includes not only the above-mentioned a-CyD, ~-CyD and ~-CyD, but so-called branched CyDs wherein one or plural glucose residues are added thereto, but ~-CyD is partic-ularly preferred. Thus, although hereinafter, the invention is described citing ~-CyD for making the description concise, it should be understood that other CyDs can be treated in the same manner and have the similar actions. When the above CyD wherein 100 % of the hydroxyl groups are acylated is more specifically expressed, it corresponds to heptakis (2,3,6-tri-0-acyl)-~-cyclodextrin.
Specific examples of the acyl groups which are referred to in the C 2 - t 8 acylation include acetyl, propanoyl, butanoyl. pentanoyl (or valeryl), hexanoyl (or caproyl), heptanoyl (or enanthyl), octanoyl (or capryloyl), dodecanoyl (or lauroyl), tetradecanoyl (or myristoyl), octadecanoyl (or stearoyl) groups, etc., and acyl groups derived from branched chain fatty acids corresponding thereto, but acyl groups derived from straight-chain fatty acids are preferably used. These acyl groups can be the same or different, but conve-nience on preparation being taken into account, it is preferred that all the acy groups are the same.
Further, if the acylated CyD used in the invention has the same acyl group, ones having 4 to 8 carbon atoms are preferred, and ones having 4 to 6 carbon atoms are particularly preferred. For example, per-C5 acylated ~-CyD has, as such, fiIm formability, and per-C4 acylated ~-CyD or per-C6 acylated ~-CyD can also be molded into fiIm, if needed by adding a fiIm forming-high molecular compound or the like, and the fiIm can conveniently be used as a pharmaceutical compo-sition for trans-mucosal or transdermal administration according to the invention.
Thus, according to the invention, the acylated CyD can readily be molded, as the form of the composi-tion, into a filmy form and a sheet-like form. Although its details are made clear later, there is a case where-in, as to the composition molded into the form of a sheet or fiIm, the release patterns of the drug somewhat 10 differ between the side of the casting surface and the side of the opposite surface, and it is also possible to choose the surface to be applied to the mucosa or cutis, in accordance with the purpose of the drug used.
As to the composition of the invention molded into a fiImy or sheet-like form as stated above, its affinity to the surface to be applied can be adjusted by treating the surface by a suitable method to cause partial deacylation. As this treating method, there can be mentioned alkali treatment or treatment with a suit-able deacylating enzyme. The thus obtained partiallydeacylated composition of the invention is preferred especially in the point that if it is administered to a mucosa under an aqueous environment, for example the oral mucosa, the retentivity of the composition on the 25 mucosa is improved. Thus, a composition wherein partial deacylation is made by surface treatment of the above composition of the invention is also provided according to the invention.
As drugs to be incorporated in the composition 30 according to the invention, any drugs including water-soluble and water-sparingly soluble ones can be used so long as they are in line with the obiect of the inven-tion, but from the standpoint that they are trans-muco-sally or transdermally administered, there can, for example, be mentioned nonsteroidal antirheumatic agents, steroids, cardiac glycosides, benzodiazepine deriva-tives, benzimidazole derivatives, piperidine deriva-tives, piperazine derivatives, imidazole derivatives and triazole derivatives. Althsugh not limited thereto, as benzimidazole derivatives, there can be mentioned thia-bendazole, fuberidazole, oxibendazole, parbendazole,cambendazole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and astemizole.
Further, as suitable piperidine derivatives, there can be mentioned bruspirilen, bimotide, penfluridol, loper-10 amide, ketanserin, levocabastine, cisapride, altanserinand ritanserin. Further, as suitable piperazine deriva-tives, there can be mentioned lidoflazine, flunarzine, mianserin, oxatomide, miofurazine and cinnarizine.
Further, as suitablé imidazole deriva~ives, ~here can be 15 mentioned metronidazole, ornidazole, ipronidazole, tindazole, isoconazole, nimorazole. primamide, methi-amide, metomidate, enilconazole, etomidate, econazole, clotrima~ole, garnidazole, cimetidine, docodazole, sulconazole, parconazole, orconazole, butoconazole, 2G triadimin~l, Ti~on~2~1e, parconazole, fluotrimazole, ketoconazole, oxyconazole, rombazole, bifonazole, oxci-metidine, fenti~onazole an~ tabrazole. Fur~her, as suitable triazole derivatives, there can be mentioned birazole, itraconazole and terconazole. Further, a nitrous acid derivatives such as, isosorbide dinitrate or nitroglycerin can al~o preferably be incorporated in the composition of the invention.
In addition to the above drugs, this invention --covers also the following drugs, which are classified 30 according to their efficacy:
analgesic and anti-inflammatory drugs such as acetylsalicylic acid, sodium diclofenac, ibu-profen, i~dometh~cin, ketoprofen, sodium meclofenamate, mefenamic acid, sodium naproxen, paracet3mol. piroxicam and sodium tolmetin;
anti-arrhythmic drugs such as procainamide HCI, qunidine sulphate and verapamil HCI;
antibacterial agents such as amoxicillin, ampicillin, benzathine penicillin, benzyl-peniciilin, cefaclor, cefadroxil, cephalexin, chloramphenicol, ciprofloxacin, clavulanic acid, clindamycin HCI, doxycycline HCI, erythromycin, sodium flucloxacillin, kanamycin sulphate, lincomycin HCI, minocycline HCI, sodium nafcillin, nalidixic acid, neomycin, norfloxacin, ofloxacin, oxacillin and potas-sium phenoxymethyl-penicillin;
anti-coagulants such as warfarin;
antidepressants such as amitriptyline HCI.
amoxapine, butriptyline HCI, clomipramine HCI, desipramine H-CI, dothiepin HCI, doxepin HCI, fluoxetine, gepirone, imipramine, lithium carbonate, mianserin HCI, milnacipran, nortriptyline HCI and paroxetine HCI;
anti-diabetic drugs such as glibenclamide;
antifungal agents such as amphotericin, clotrimazole, econazole, fluconazole, flucy-tosine, griseofulvin, itraconazole, ketocona-zole, miconazole nitrate and nystatin;
antihistamines such as astemizole, cinnari-zine, cyproheptadine HCI, flunarizine, oxatomide~ promethazine and terfenadine;
anti-hypertensive drugs such as captopril, enalapril, ketanserin, lisinopril, minoxidil, prazosin HCI, ramipril and reserpine;
anti-muscarinic agents such as atropine sul-phate and hyoscine;
antivirals such as acyclovir, AZT, ddC, ddl, ganciclovir, loviride, tivirapine, 3TC, dela-virdine, indinavir, nelfinavir, ritonavir and saquinavir;
sedating agents such as alprazolam, buspirone HCI, chlordiazepoxide HCI, chlorpromazine, clozapine, diazepam, flupenthixol HCI, fluphe-nazine, flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine, risperidone, selfotel, seroquel, sulpiride, temazepam, thiothixene, triazolam, trifluperidol and ziprasidone;
anti-stroke agents such as lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil and remacemide;
anti-migraine drugs such as alniditan and sumatriptan;
beta-adrenoreptor blocking agents such as atenolol, carvedilol, metoprolol, nebivolol and propranolol;
cardiac inotropic agents such as digitoxin, digoxin and miIrinone;
corticosteroids such as beclomethansone dipro-pionate, betamethasone, dexamethasone, hydro-cortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
disinfectants such as chlorhexidine;
diuretics such as acetazolamide, frusemide, hydrochlorothiazide and isosorbide;
anti-Parkinsonian drugs such as bromocryptine mesylate, levodopa and selegiline HCI;
enzymes or essential oils such as anethole, anise oil, caraway, cardamom, cassia oil, cinelole, cinnamon oil, clove oil, coriander oil, dementholised mint oil, dill oil, euca-lyptus oil, eugenol, ginger, lemon oil, mus-tard oil, neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol and thyme;
gastro-intestinal agents such as cimetidine, cisapride, clebopride, diphenoxylate HCI, domperidone, famotidine, lansoprazole, loper-amide HCI, loperamide oxide, mesalazine, metoclopramide HCI, mosapride, olsalazine, omeprazole, ranitidine, rabeprazole, ridogrel and sulphasalazine;
haemostatics such as aminocaproic acid;
lipid regulating agents such as lovastatin, pravastatin, probucol and simvastatin;
local anaesthetics such as benzocaine and llgnocalne;
opioid analgesics such as buprenorphine HCI, codeine, dextromoramide and dihydrocodeine;
parasympathomimetics such as galanthamine, neostigmine, physostymine, tacrine, donepezil, ENA 713 (exelon) and xanomeline; and vasodilators such as amlodipine, buflomedil, amyl nitrite, diItiazem, dipyridamole, gly-ceryl trinitrate, isosorbide dinitrate, lido-flazine, molsidomine, nicardipine, nifedipine, oxpentifylline and pentaerythritol tetra-nitrate.
In the composition according to the invention, the compounding ratio between the peracylated CyD and the drug can be any ratio so long as it meets the ob-ject, but from the standpoint to control the releas-ability of the drug from the composition, it is possible 20 to choose, as the ratio of the peracylated CyD to the drug, 1:4 to 4:1, preferably 1:2 to 2:1, as molar ratio.
Further, the composition of the invention can, if necessary, contain other pharmaceutically acceptable auxiliaries or additives in such a range that the object 25 of the invention is not adversely influenced. Examples of such auxiliaries or additives include absorption enhancers or skin permeability enhancers for drugs, physical property improvers, stabilizers, etc.
Examples of absorption enhancers include 1-dodecylhexahydro-2H-azepin-2-one, fatty acids such as oleic acid, pyrrolidone derivatives such as N-methyl-pyrrolidone, thioglycolates such as potassium thiogly-colate or calcium thioglycolate, fatty acid alcohol esters such as diisopropyl adipate, enamines, salicylic 35 acid derivatives, sodium caprate, menthol, and the like.
The absorption propoters may be added to the composition in about up to 0.5%, preferably in about 1% to about 10%, by weight per total weight of the composition.
Examples of physical property improvers include surfac-tants such as polyoxyethylene fatty acid esters, poly-oxyethylene polyoxypropylene block copolymers and fattyacid glycerol esters, thickeners such as xanthane gum, carboxyvinyl polymers, sodium carboxymethylcellulose, polyvinyl pyrrolidone, methylcellulose, hydroxypropy cellulose and propylcellulose, and colorants such as 10 food dyes and iron oxides. Examples of stabilizers include antioxidants such as ascorbic acid, ascorbic palmitate, thioglycerol, dl-~-tocophelol, butylhydroxy-toluene, butylhydroxyanisole and propyl gallate, and preservatives such as benzalkonium chloride, sorbic acid and paraoxybenzoic acid esters such as methyl paraben, ethylparaben and benzylalcohol.
The composition according to the invention can be produced by a formulation method known per se, but can preferably be produced as follows.
Peracylated ~-CyD and a drug are dissolved in an organic solvent incompatible with water, this solu-tion is added dropwise onto a water surface and devel-oped, and the solvent is volatilized to give a fiImy composition having adhesion. In this connection, as conditions for removing the organic solvent, there can be chosen a condition fit for the drug such as ordinary pressure and ordinary temperature, heating under ordi-nary pressure or heating under reduced pressure or the like. Further, it is possible to obtain a fiImy compo-sition having adhesion by dissolving peracylated ~-CyD
and a drug in an organic solvent, adding dropwise the solution onto aluminum foil, polyethylene terephthalate film, polystyrene fiIm or the like, developing it, and volatilizing the solvent in the same manner as mentioned above. If such a process is used and pervaleryl (C 5) -~-CyD is used as the peracylated ~-CyD, a transparent filmy composition can be obtained without using other additives.
It is not disclosed in prior art literatures that such a fiImy composition can be obtained, and herein, there is provided, as another embodiment of the invention, a process for preparing a sheet-like or filmy pharmaceutical composition for trans-mucosal or trans-dermal administration which contains a step of casting a solution or suspension containing a per-C 2 -1 8 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
Further, it is possible to obtain a powdery or granular composition by dissolving peracylated ~-CyD and a drug in an organic solvent, and distilling off the solvent by a rotary evaporator or the like. It is also possible to obtain a composition by heat melting per-acylated ~-CyD and a drug, cooling the melt, and if necessary, grinding the cooled matter.
Certain peracylated CyDs can be produced 20 according to the process described in the above Chem.
Pharm. Bull., 43 (1995), 130-136, and the acylated derivatives of CyDs used in the invention canr for example, be produced by dissolving ~-CyD in anhydrous pyridine, adding an organic acid corresponding to the length of acyl group such as acetic anhydride or valeric anhydride at room temperature and under an anhydrous condition, and stirring with heating to around 80~C.
After confirmation of the completion of the reaction with thin layer chromatography, the reaction solution is 30 added to ice-water, the precipitate deposited and the oily matter were extracted with a solvent such as chlo-roform, the obtained extraction product is concentrated over anhydrous magnesium sulfate, and the concentrate is subjected to separation and purification by silica gel chromatography. Further, the purified product is dis-solved in chloroform, the solution is sufficiently CA 02209862 l997-07-04 washed with an aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate, the solvent is distilled off, and further, the residue is recrystal-lized from methanol to give purified acylated ~-CyD.
In the composition according to the invention, the peracylated cyclodextrin and the drug exist in such a state that they are in a molecular state and can interact (e.g., the drug is clathrated in the CyD mole-cule), and the outside of the cyclodextrin molecule 10 exhibits hydrophobicity and is good in contact with the skin or mucous membrane, and moreover, gives almost na irritation on them. Therefore, the drug is directly released from the composition to the cutis or mucosa.
Namely, the movement of the drug molecule and the perme-ation thereof into the mucosa are possible without theaid of water or a solvent or the like.
Thus, according to the invention, there is provided a pharmaceutical composition for trans-mucosal or transdermal administration which is safe and excel-lent in the release behavior of the drug and skin perme-ability.
Hereinafter, examples are mentioned, aiming to describe the invention more specifically.
ExamPle (comParison) 1 Adhesive characteristic of PervalerYI-~-cYclodextrin Pervaleryl-~-cyclodextrin (TV-~-CyD)-contain-ing absolute ethanol solution (concentration: 150 mg/ml) was added dropwise onto a backing membrane (poly-30 ethylene terephthalate film) using a microsyringe, andallowed to stand at 25~C for 24 hours to evaporate ethanol, whereby fiIms of TV-~-CyD having adhesion were obtained.
The detaching force on the fiIms of TV-~-CyD
and on the fiIms derived from various hydrophilic macro-molecules (hydroxypropylcellulose (HPC), hydroxypropyl-CA 02209862 l997-07-04 methylcellulose (HPMC) and polyhydroxyethyl methacrylate (PHEMA)) was measured using a probe tack tester (pro-duced by Rigaku Kogyo Co.). The results are shown in Fig. 1. The fiIms of hydrophilic macromolecules were prepared as described with respect to TV-~-CyD. The drawing shows that TV-~-CyD is the strongest in adhe-sion.
ExamDle (comParison) 2 Cutis irritativeness of ~er-TV-~-CvD
There was stuck 150 mg of TV-~-CyD, in the shape of a circle with a diameter of 20 cm, on the back of female hairless mice at the age of around 7 weeks (weight: 50-60 g), and 16 hours later, the cutis was extirpated. The extirpated cutis was fixed with 20 %
neutrally-buffered formalin solution and embedded in paraffin according to a usual manner, and tissue sec-tions were prepared using a microtome. These sections were double stained with haematoxylin and Eosine, and observed by a light microscope. Untreated cutis was 20 used as control. Moreover, a commercially available adhesive tape for patch test was applied on the same mice under the same condition, and, thereafter. the cutis tissue of the applied portion was extirpated for comparison. In the case of TV-~-CyD, there was observed peeling of corneum in the same degree as in the case of the commercially available adhesive tape. Other sites (control), however, showed no abnormality such as in-flammatory cellular infiItration.
Examples (invention) 3 to 6 30 Adhesive characteristic of adhesive comDositions and adhesive comPositions containin~ an absor~tion enhancer Isosorbide dinitrate (ISDN) (3.4-6.7 mg) was dissolved in a TV-~-CyD-containing ethanol solution (concentration: 150 mg/ml), so as to give the following 35 molar ratios, respectively, and each solution was added dropwise onto a backing membrane (polyethylene tere-phthalate film) using a microsyringe, and allowed to stand at 25~C for 24 hours to evaporate ethanol, whereby an ISDN/TV-~-CyD composition having adhesion was ob-tained.
Isosorbide dinitrate (ISDN) (3.4-6.7 mg) was dissolved in a trivaleryl-~-cyclodextrin (TV-~-CyD)-cont aining ethanol solution (concentration: 150 mg/ml), respectively, and oleic acid (OA) was added (concentra-tion: 4 w/v%). Each of the resultant solutions was 10 added dropwise onto a backing membrane (polyethylene terephthalate film) using a microsyringe, and allowed to stand at 25~C for 24 hours to evaporate ethanol, whereby an ISDN/TV-~-CyD/OA containing the absorption enhancer and having adhesion was obtained.
The adhesion of ISDN/TV-~-CyD (molar ratio 1/1: Example 3; 2/1: Example 5), ISDN/TV-~-CyD/OA
(molar ratio 1/1/0.2: Example 4; 2/1/0.2: Example 6), and a commercially available isosorbide dinitrate prepa-ration (Frandle Tape S, comparison) was measured using a 20 probe tack tester (produced by Rigaku Kogyo Co.), and the results are shown in Fig. 2. As is seen apparently in the above, the present adhesive composition exhibits good adhesion even if it contains the absorption enhan-cer.
ExamPles (invention) 7 to 10 Dru~ release from adhesive comoositions ISDN/TV-~-CyDs having different diameters (diameter: 1 cm, 2 cm and 3 cm) were prepared in the same manner as in Examples 3 to 6. Drug release was 30 measured according to the Second Method (Paddle Method) of Dissolution Test in the Japan Pharmacopeia Xll using an automatic dissolution test apparatus (see Fig.5), in the following manner. ISDN/TV-~-CyD was fixed on an aluminum plate and put in a jacket beaker (inside diame-35 ter 5 cm, content volume 200 ml) through which circulat-ing water of 34~C was passed, and, then, 50 ml of deaerated eluent was introduced into said jacket beaker.
The I SDN concentration was measured by a circulating UV
detector (produced by SHI MADZU CORPORAT I ON) . For com-parison, measurement was conducted on Frandle Tape S in the same manner. The results are shown in Fig. 3. The I SDN/TV-~-CyD having a diameter of 3 cm exhibited a release equivalent to Frandle Tape S, and, thus, a good drug release was shown.
Examoles (invention) 11 to 12 10 Transdermal administration from cohesive comDosition I SDN/TV-~-CyD (molar ratio 2/1: Example 11) and I SDN/TV-~-CyD/OA (molar ratio 1/1/0.2: Example 12) were prepared in the same manner as in Examples 3 to 6.
Wister male rats (weight: about 240 g) whose hair of 15 the abdominal part had been removed under anesthetiza-tion were fixed on their backs, and the above I SDN/TV-~-CyD or I SDN/TV-~-CyD/OA was stuck on the unwounded part of each rat. Blood (0.6 ml) was taken with the lapse of time from the cervical vein using a syringe treated with heparin. To 0.2 ml of plasma from each of the obtained bloods, there was added 0.5 ml of 0.5 M phosphate buf-fer, and extraction was conducted with 6 ml of chloro-form. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in mobile phase of 25 methanol/water (1:4 v/v), and the ISDN concentration was measured by HPLC. The changes with time lapse of the I SDN concentration in the plasma after the administra-tion to the abdominal parts of the rats are shown in Fig. 4. The values in the results are expressed as the 30 mean + SE (n = 3).
Each of the fiIms maintained an ISDN concen-tration in the plasma of 40 ng/ml or more, which is an effective concentrat;on, for 12 hours or more.
.
Conditions of the above High-performance Liquid Chroma-tography (HPLC) were as follows:
Pump: 655 A-11 Type HPLC made by Hitachi Seisakusho K.K.
UV Detector: 655 A Type Wave Variable UV
Monitor made by Hitachi Seisakusho K.K.
Integrator: D-2500 Type Chromato-lntegrator made by Hitachi Seisakusho K.K.
Column: Shiseido Capsule PAK C8 SG120 o A (5 ~m, 4.6 mm ~ x 300 mm) Mobile Phase: methanol/water (1:4 v/v) Flow Rate: 1.0 ml/min.
Measured Wave Length: 210 nm Example (invention) 13 Pharmaceutical com~osition a~licable to oral mucous membrane containin~ triamcinolone White crystals (50 g) of perbutanoyl-~-cyclo-dextrin (TB-~-CyD) were dissolved in ethanol (200 ml), 20 and, then, triamcinolone (12.6 g) was added. After stirring, drying with heating was conducted under re-duced pressure at 60~C for 3 hours. To the resultant powder (62 g), there were added lactose (120 g), corn starch (40 g), microcrystalline cellulose (Avicel~
PH102: 18 g), hydroxypropylmethylcellulose [HPMC
(TC-5.S: 6 g)] and magnesium stearate (0.04 g), and the mixture was uniformly mixed and tableted to give tablets administrable to oral mucosa.
A tablet contained the following components:
5 mg of triamcinolone 20 mg of TB-~-CyD
17 mg of lactose 7.5 mg of Avicel~ PH102 2.5 mg of HPMC (TC-5.S), and trace amount of magnesium stearate Total: 102 mg The obtained tablets were tested for their characteristics (contents, fragileness and weight devia-tion) according to Preparation General Rules of The Japan Pharmacopeia Xll, and as a result they are found to be fit for all the test items. They were good in adhesion to the cheek, and adhesion was recognized to be durable. Further, there was no irritation to mucosa at the time of application.
Claims (18)
1. A pharmaceutical composition for the transmucosal or transdermal administration comprising a per-C2-18 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
2. A pharmaceutical composition according to claim 1 wherein the per-C2-18 acylated cyclodextrin is at least one of per-C2-18 acylated .beta.-cyclodextrins.
3. A pharmaceutical composition according to claim 1 wherein the acylated cyclodextrin is a per-C4-6 acylated .beta.-cyclodextrin.
4. A pharmaceutical composition according to claim 1 wherein the drug is selected from the group consisting of nonsteroidal antirheumatic agents, steroids, cardiac glycosides, benzodiazepine derivatives, benzimidazole derivatives, piperidine derivatives, piperazine derivatives, imidazole derivatives and triazole derivatives.
5. A pharmaceutical composition according to claim 1 wherein the molar ratio of the acylated cyclodextrin to the drug is 1:4 to 4:1.
6. A pharmaceutical composition for the transmucosal or transdermal administration comprising a per-C2-18 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug, said composition being in the form of a sheet or film.
7. A pharmaceutical composition according to claim 6 wherein the per-C2-18 acylated cyclodextrin is at least one of per-C2-18 acylated .beta.-cyclodextrins.
8. A pharmaceutical composition according to claim 6 wherein the acylated cyclodextrin is a per-C4-6 acylated .beta.-cyclodextrin.
9. A pharmaceutical composition according to claim 6 wherein the drug is selected from the group consisting of nonsteroidal antirheumatic agents, steroids, cardiac glycosides, benzodiazepine derivatives, benzimidazole derivatives, piperidine derivatives, piperazine derivatives, imidazole derivatives and triazole derivatives.
10. A pharmaceutical composition according to claim 6 on which partial deacylation is made by surface treatment.
11. A pharmaceutical composition according to claim 1 which further contains an absorption enhancer of the drug.
12. A pharmaceutical composition according to claim 6 which further contains an absorption enhancer of the drug.
13. A method for the trans-mucosal or transdermal administration of a drug. which comprises applying a pharmaceutical composition to the mucosa or cutis of an individual who needs to be treated with the drug, said composition comprising a per-C2 - 18 acylated cyclodextrin and the drug.
14. A method according to claim 13 wherein the acylated cyclodextrin is a per-C4 - 6 acylated .beta.-cyclodextrin.
15. A method according to claim 13 wherein the composition is in the form of a sheet or film.
16. A method according to claim 13 wherein the composition further contains an absorption enhancer of the drug.
17. A process for preparing a sheet-like or filmy pharmaceutical composition for trans-mucosal or transdermal administration which contains a step of casting a solution or suspension containing a per-C2 18 acylated cyclodextrin as a solubilizing agent, adsorbent or clathrating agent, and a drug.
18. A process according to claim 17 wherein the acylated cyclodextrin is a per-C4 6 acylated .beta.-cyclodextrin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP356054/96 | 1996-12-25 | ||
| JP8356054A JPH10194996A (en) | 1996-12-25 | 1996-12-25 | Acylated cyclodextrin-containing pharmaceutical composition |
| US08/886,934 US5904929A (en) | 1996-12-25 | 1997-07-02 | Acylated cyclodextrin-containing pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2209862A1 true CA2209862A1 (en) | 1998-06-25 |
Family
ID=26580367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002209862A Abandoned CA2209862A1 (en) | 1996-12-25 | 1997-07-04 | Acylated cyclodextrin-containing pharmaceutical composition |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US5904929A (en) |
| JP (1) | JPH10194996A (en) |
| CA (1) | CA2209862A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA57734C2 (en) * | 1996-05-07 | 2003-07-15 | Пфайзер Інк. | Arylheterocyclic inclusion complexes |
| EP1117384A1 (en) * | 1998-10-01 | 2001-07-25 | Elan Pharma International Limited | Controlled release nanoparticulate compositions |
| US20080213378A1 (en) * | 1998-10-01 | 2008-09-04 | Elan Pharma International, Ltd. | Nanoparticulate statin formulations and novel statin combinations |
| US8293277B2 (en) * | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
| US20040013613A1 (en) * | 2001-05-18 | 2004-01-22 | Jain Rajeev A | Rapidly disintegrating solid oral dosage form |
| US7521068B2 (en) * | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
| US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
| US20040141925A1 (en) * | 1998-11-12 | 2004-07-22 | Elan Pharma International Ltd. | Novel triamcinolone compositions |
| US20040115134A1 (en) * | 1999-06-22 | 2004-06-17 | Elan Pharma International Ltd. | Novel nifedipine compositions |
| FR2795645B1 (en) * | 1999-06-30 | 2001-09-21 | Union Pharma Scient Appl | NEW PHARMACEUTICAL ASSOCIATION WITH ANALGESIC ACTIVITY |
| EP1109806B8 (en) * | 1999-07-01 | 2003-10-29 | Italfarmaco S.p.A. | Complexes of paroxetine, with cyclodextrins or cyclodextrin derivates |
| US6312712B1 (en) * | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6312723B1 (en) * | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US7503493B2 (en) * | 1999-10-25 | 2009-03-17 | Silverbrook Research Pty Ltd | Method and system for digitizing freehand graphics with user-selected properties |
| AU2001255709A1 (en) * | 2000-05-11 | 2001-11-20 | Eastman Chemical Company | Acylated cyclodextrin guest inclusion complexes |
| US20040156872A1 (en) * | 2000-05-18 | 2004-08-12 | Elan Pharma International Ltd. | Novel nimesulide compositions |
| US7198795B2 (en) | 2000-09-21 | 2007-04-03 | Elan Pharma International Ltd. | In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions |
| US6566556B2 (en) * | 2000-12-19 | 2003-05-20 | Nippon Shokubai Co., Ltd. | Method for production of alkanolamine and apparatus therefor |
| WO2003028718A1 (en) * | 2001-10-01 | 2003-04-10 | Smithkline Beecham Corporation | Novel formulations of carvedilol |
| US7141540B2 (en) * | 2001-11-30 | 2006-11-28 | Genta Salus Llc | Cyclodextrin grafted biocompatible amphilphilic polymer and methods of preparation and use thereof |
| ATE464880T1 (en) * | 2002-02-04 | 2010-05-15 | Elan Pharma Int Ltd | MEDICINAL NANOPARTICLES WITH LYSOZYME SURFACE STABILIZER |
| US20040101566A1 (en) * | 2002-02-04 | 2004-05-27 | Elan Pharma International Limited | Novel benzoyl peroxide compositions |
| JPWO2003066100A1 (en) * | 2002-02-07 | 2005-05-26 | エーザイ株式会社 | Hair growth promoter, preparation for transdermal application, and method for promoting hair growth |
| US20040254146A1 (en) * | 2002-05-21 | 2004-12-16 | Nastech Pharmaceutical Company Inc. | Carboxylate salts of galantamine and their pharmaceutical use |
| US20040258757A1 (en) * | 2002-07-16 | 2004-12-23 | Elan Pharma International, Ltd. | Liquid dosage compositions of stable nanoparticulate active agents |
| DE60327225D1 (en) * | 2002-08-20 | 2009-05-28 | Bristol Myers Squibb Co | ARIPIPRAZOL COMPLEX FORMULATION AND METHOD |
| US7166671B2 (en) * | 2002-12-10 | 2007-01-23 | Cellresin Technologies, Llc | Grafted cyclodextrin |
| US7385004B2 (en) * | 2002-12-10 | 2008-06-10 | Cellresin Technologies, Llc | Enhanced lubrication in polyolefin closure with polyolefin grafted cyclodextrin |
| US8129450B2 (en) | 2002-12-10 | 2012-03-06 | Cellresin Technologies, Llc | Articles having a polymer grafted cyclodextrin |
| DE10338544B4 (en) * | 2003-08-19 | 2017-08-31 | Janssen Pharmaceutica N.V. | Buccal formulations of galanthamine and their applications |
| ATE480592T1 (en) * | 2004-05-24 | 2010-09-15 | Cellresin Tech Llc | AMPHOTERE GRAFTED BARRIER MATERIALS |
| JP2008512471A (en) * | 2004-09-08 | 2008-04-24 | ダーマトレンズ，インコーポレイティド | Transdermal delivery of hydrophobic bioactive substances |
| US20070191306A1 (en) * | 2005-08-17 | 2007-08-16 | Bristol-Myers Squibb Company | FACTOR Xa INHIBITOR FORMULATION AND METHOD |
| BRPI0600636A (en) * | 2006-02-03 | 2007-10-30 | Univ Minas Gerais | process for formulations of angiotensin converting enzyme inhibitors and product |
| JP2009534388A (en) | 2006-04-18 | 2009-09-24 | イーケーアール セラピューティクス， インク． | Premix immediate use pharmaceutical formulation |
| US8641876B2 (en) * | 2006-04-19 | 2014-02-04 | Ellen T. Chen | Nanopore array structured devices for biosensing and energy storage |
| DK2374450T3 (en) * | 2010-04-06 | 2012-07-23 | Lundbeck & Co As H | Flupentixol compositions |
| TW201332572A (en) | 2011-12-28 | 2013-08-16 | Otsuka Pharma Co Ltd | Pharmaceutical preparation comprising substituted β -cyclodextrin |
| CN115252585A (en) * | 2021-04-13 | 2022-11-01 | 上海博志研新药物技术有限公司 | Brexpiprazole oral solution membrane-coated composition, preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4414128A1 (en) * | 1994-04-22 | 1995-10-26 | Consortium Elektrochem Ind | Partially acylated beta-cyclodextrins |
-
1996
- 1996-12-25 JP JP8356054A patent/JPH10194996A/en not_active Withdrawn
-
1997
- 1997-07-02 US US08/886,934 patent/US5904929A/en not_active Expired - Fee Related
- 1997-07-04 CA CA002209862A patent/CA2209862A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US5904929A (en) | 1999-05-18 |
| JPH10194996A (en) | 1998-07-28 |
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Legal Events
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| FZDE | Discontinued |