TW200427464A - Transmucosal and transdermal medicaments with improved active substance absorption - Google Patents

Abstract

Medicaments for transmucosal or transdermal administration of active substances are characterized in that in order to improve active substance absorption they contain at least one substance form the group of the monoterpenes an at least one substance from the group of the polyalcohols.

Description

200427464

V. Description of the invention (l) [Technical field to which the invention belongs The present invention relates to the use of active substances for transmucosal substances' This medicine contains a combination of adjuvants (promoters) that enhance or accelerate the absorption of active substances . 1、1 = use of earthworm percutaneous substance, administration of active substance, and preparation: preparation prepared in the form of skin administration, this preparation contains aspiration promoting :: Tim: [previous technique] transmucosal administration of active substance, Especially through the oral mucosal buccal administration form), from the point of view of the cover, such as JJ ^ ^ 盖 盖 bias ^ galenic) is advantageous, because it can achieve a rapid start-up effect, and . Bioavailability. Thus, people have used spray and sublingual lozenges to perform such administration. The thin film system "wafer" is known as a novel administration form for oral administration via the mouth, mucous membranes, or cheeks. These thin scum-like systems can give mucoadhesive properties so that mold can be firmly attached to the mucosa during administration, such as the cheek (or even gum) mucosa. In addition, the thin film system can be made into a degradable, partially degraded, or non-degradable film by appropriately selecting the ingredients of the formulation. After the film-like system is applied in the mouth, the active substance contained in the system is released to its environment and partially absorbed through the mucosa, but partly ^

Page 5 200427464 V. Description of the Invention (2) Saliva was swallowed. The amount of released active material that is swallowed cannot be absorbed by the mucous membrane, thus reducing the bioavailability of the active material. To avoid this disadvantage, the mucosal absorption of the active substance needs to be as fast as possible. The problem of improving the absorption of active substances also exists in the transdermal therapeutic system, which promotes the controlled administration of medicinal active substances over an extended period of time, which usually lasts for hours or days. Since the skin is a barrier for many active substances', transdermal drugs, it is extremely important to increase the absorption of the active substance through the skin. [Summary of the Invention] Therefore, the object of the present invention is to indicate a substance or a mixture of substances (so-called "promoter") that enhances the transmucosal or transdermal absorption of an active substance, and is characterized by having a transmucosal or transmembrane of an active substance Dermal absorption drugs. [Embodiment] According to the scope of the main patent application, a drug for transmucosal or transdermal administration is used to solve this problem, which contains at least one substance from the monoterpenes group, and at least one from the same time Substances of the Polyol Group. Adding a combination of these substances results in an increase in the absorption of the active substance through the oral mucosa. In addition, it was found that the aforementioned promotion was added to a drug for transdermal administration.

200427464

The combination of agents and substances includes at least one of the substances of the polyalcohol group, which promotes the percutaneous formation of active substances related to the absorption of the active substance from the monoterpene group, and thus plays the role of a drug. And gains from it. The substance of the present invention, with at least one from the mucosa and transdermal actives, is not intended to be limited by any theory. Because the single-box ene-Fuhe — "the function of the clam is' can be reduced, it will be faster, military: expansion of the Function, so that the active substance :: is transported away more decisively. As for the polyhydric alcohols, it also exists as a plasticizer

JF column, the germ line belongs to the monoterpene group that is particularly suitable: Monadienes, such as myrcen, ocimen; ί dienes, such as α_pinene (camene) Limonene, phellanderene, pinene, sabinene, terpinene; fine ifc fines, such as Cymol; alcoholic monosene , Such as borneol (borne〇1), geraniol (carve〇l), dihydrocarvitol, geraniol, linalool

(1 i na 1 001), perillyl alcohol, sab i nene hydrate, terpineol; a singular group; gene, such as camphor, carvone, Citric acid, cumine aldehyde, dihydrocarvone, fenchone, safranal, thujone; — phenolic monoterpenes, such as anethol Eugenol

Page 7 200427464 V. Description of the invention (4) (Carvacrol), clove oil test (eUgen〇i), eucalyptol, methyl cavicoi, thymol, trans-anise Brain; — complex phenolic monoterpenes, such as picrocrocin; — compounds derived from monoterpenes, such as 5_fluorenyloxy- (2_fluorenyl-butanyloxy) -1- Acrylic benzene, propylene-tetramethoxybenzene, anisaldehyde, anisketone, apiol, eiemicin, hydroxyanisole, butyric acid, ginger _ (zingerone); ~ Propylbenzene, such as 5-methoxy- (2-fluorenyl-butanyloxy) -1-propenebenzene, propanyl-tetramethylfluorenylbenzene, fennel brain, cumine aldehyde, sandalwood Balsam, estragol, eugenol, eucalyptol, foenicui in, hydroxyanisole methyl butyrate, fluorenyl cavi col, myristicin, safrol, ginger . Polyols that can be used are preferably dihydric-alcohols such as ethylene glycol, propylene glycol, butanediol, etc., but can also be tri-hydrogen or poly-hydrogen alcohols, especially glycerin. Among alcohols with a lot of hydrogen, polyvinyl alcohol must be taken into consideration. These can simultaneously function as a matrix former ', such as as a component involved in the formation of a solid matrix of a drug. According to a preferred embodiment of the present invention, there is further provided a medicament-promoting agent mixture, which contains a combination of two or more substances derived from a monoterpene group, and / or two or more compounds derived from a polyol group Group of matter

1

Page 8 No. 200427464 V. Description of Invention (5) Combination. In any case, the accelerator mixture A group of substances, and at least one from the poly "at least one of the monoterpenes from the cheek group. Preferably, menthol or menthol is selected from the group consisting of propylene glycol, butylene glycol and ethylene diene, and early cylinderene mixtures and combinations, and is used as a promoter mixture. It was further found that at least one polyalcohol group of ^, such as 杲 a. Or η I, industrial mucosa, or transdermal M, had provitamin B5 and / or-or a plurality of ^ substances additionally contained other good Active substance absorption. 5 salt, you can achieve the right medicine in the special medical music formulation right + 忐 and 忐 dan r 4 the accelerator substance 'better and right 殂 Chengli (relative to dry basis): 1 Category: 〇5-40fango ° / v 5: 2. % By weight; ° "The better is 3, the weight" ... especially preferred 2 ^ 5 '"%' the better is 3-30% by weight, especially 0 zu reset%; the better the better ^ prime β5 or vitamin B5 salt members: 〇5—40 ％ by weight I% 'Special 轫 4 本 Γ;-〇rv 土-° Fortunate father 3-The following are better 5-20% by weight 30 Yes -3 = !: It is preferable to have a substantially solid substrate A, a substrate-forming substance, and an absorption-enhancing substance of at least one active substance f. The substrate may contain the aforementioned activity

200427464

The present invention further relates to a mucoadhesive drug, which is degradable in an aqueous medium or a physiological adhesive film. Appropriate soluble for this purpose and / or known to those skilled in the art. Shellfish formation and adjuvants are well known. It is possible to release the active substance to dissolve the formula 4 such as " ϊ =, individual ΐ degradability ', in an aqueous medium, eg: saliva: example film Can be deployed as an immediate or slow release system as appropriate. Or something ... formulated in an aqueous medium-In addition to water, the "aqueous medium" also needs to understand especially physiological fluids, especially saliva. The transmucosal, in particular, film-like drugs of the present invention are preferably formulated into an oral formulation. The present invention further comprises medicaments for vaginal or rectal use. 200427464 V. Description of the invention (7) Manufacturing of pharmaceuticals for transporting active substances through mucosa, formulas, and matrix-forming products suitable for this purpose] Others are known in the form of film-shaped administration. "Matrix II adjuvants and solvents are not polymers, and these substances are suitable for referring to a special semi-solid matrix (basic structure). This matrix is a solid or a reservoir for sexual substances. The matrix forms components The weight of stone 2 is 95% of the activity of the temple, and the best is 15_70%. The dry knife base of the whole drug is better than 10. The matrix-forming polymer considered is, in particular, polyvinyl alcohol. (PVA), polyethylene oxide, 、 · U ^ MC)? P), propyl cellulose (HPC), marginal methyl cellulose sodium , Methylcellulose (HEC), :: Base = Vitamine (HPEC), glycans, dian powder and its derivatives, gelatin, polyvinylpyrrolidone (pvp), gum arabic, fullulan Or acrylates. Mixtures of two or more of the above polytheta compounds can also be used. In principle, the adjuvants τ and iridium used can be tolerated by those skilled in the art. The following groups of substances are used The more favorable: fillers, such as, colorants, such as quinine yellow τ%, decomposition agents (wicUng agent), which introduces water In the mass, and the matrix is opened by internal explosion, such as aerosol (aer0Sil); emulsifiers, such as Tween (polyethoxylated fatty acid sorbitan vinegar), Brij (polyethoxylated fatty alcohol); sweeteners, Aspar

200427464 V. Description of the invention (8) Sweet cyclohexylamino lutein acid sales, sugar selection · Fer glycerol; preservatives, such as sorbus: or;:, such as coffee (polyethylene glycol) other content 'better Those who can be up to 30 weight f, surname antioxidants. These amounts are based on the dry basis of the whole drug. "Especially, the content of 1 to 20 weight active substance is usually from 0.05 to ^ weight%, particularly preferably 5 to 30 weight%, more preferably 1 to The total thickness of the transmucosal drug is based on the dry base of the whole drug, 5ram, preferably 30, to 2mm, and the best film-like, can be 5, to be specially made into a round, oval Tong U # " 1 to 1 !! ^. Flat shape, or any shape you want to round. = Tower f, quadrilateral, polygonal piece. " The special music is usually regarded as "thin sawn soil made by transmucosal administration of the drug of the present invention, $ A 4 silk," and the preparation method is generally to first prepare the coated substrate with 7 daggers, alcohols or other solvents. = Without water = Beisheng; components, and possible additives. Application of coatings), roller application, spraying with a knife [doctor · Sex brace and dry welding, so an amine resisting dressing method is formed. 'Coated to 〆October when the size is: ^ layer. This film was then divided into a structure with suitable = bright forward-step on active matter (TTS) page 12 200427464 V. Description of the invention (9), with the matrix Substance and its preparation method, Mita μ A Appropriate adjuvant for this purpose and suitable ^ m) k ^ ifn / ik 、 α are known to those skilled in the art. Preferably, the leather table material is made pressure sensitive and attached to The system of the skin. The typical hand of TTS spreads into the intended, sexual-the lining (such as the reservoir connected to it,:,-containing active substances)

Film), silicidated r. A torn protective layer (such as PE film or PETP) (1C〇nized) or fluorite (Si iconized)) λ m ^ tte ^ ® ^ Side, Mody Storage-The interlayer disks are implemented separately on the skin-contacting side of the active substance depot before use. Applicable to the following groups: Propionate propene, copolymers of propylene, silicone adhesives, multilayers. Reuse to 70 for the group: fiber, ethyl acetate, styrene acrylonitrile adhesive compound. These polymers in%, the polymers used to build the active substance reservoir are special polyacrylates, poly (meth) acrylic derivatives, especially methyl and ethyl cellulose acetate, natural and synthetic rubbers, such as ethylene -Butadiene block copolymer, isoprene rubber, butyl rubber or neo-flat rubber and hot melt adhesive. Advantageously, it is also possible to make the polymer matrix of the active substance store at a content of preferably 10 to 90% by weight, each based on the dry basis of the total weight of TTS. In particular, the above-mentioned polymer 4 monolayer from the acid compound, povidin, isobutylene-diene block copolymer, pressure-sensitive polymerization, or the 'better 20' active substance reservoir of the TTS of the present invention can be further Contains mostly additives, such as self-solvent, solvent, plastic or 刎%

200427464

(tacluhers), pH regulators, antioxidants and preservatives Suitable substances for this purpose are those skilled in the art. : The content of the second-living substance is preferably from 0.5 to 50% by weight, particularly preferably = 30% by weight, each based on the dry basis of the full weight of TTS. "、 The production of the TTS of the present invention can be carried out by dissolving or suspending an active substance and a matrix into a polymer, dissolving or suspending in a suitable solvent or solvent mixture, and then coating the obtained coated substrate. On a suitable support, for example, a plastic film with a polysiloxane layer is provided. It is continued to dry and volatilize the solvent part, and the substrate layer containing the active substance is subsequently attached with another layer, which will then form a TTS. Lining. Individual TTS is made by laminating a flat-shaped object with a desired geometry and size (for example, 2 to 50 cm2). When the active substance is intended to be transdermal through the drug according to the invention In the case of transmucosal administration, in principle, all compounds or substance mixtures which have a preventive or therapeutic effect in humans or animals can be considered. It can be, in particular, derived from the following groups: Agents used to treat infectious virostatics, analgelsics, such as 17 fentanyl, bUprenorphine, anesthetics; anorectics; activity for treating arthritis and asthma Anti-convulsants; anti-depressants; anti-diabetics; anti-histamines; antidiarrheals; anti-migraine, anti-nausea and retching, and motion sickness agents, such as scopolamine (Scopolamine) and ondansetron

200427464 V. Description of the invention (π) (ondansetron); anti-neoplastic agent; anti-Parkinson's disease agent; antipsychotic agent; antipyretic agent; antispasmodic agent; antiacetylcholine agent; antiulcer agent, such as ranitidin; Sympathomimetic agents; sympathomimetic agents, such as nifedipi η; /? Blockers; / 3 antagonists; antiarrhythmic drugs; antihypertensive agents, such as atenolol (Atenolol), ACE inhibitors, such as enalapril; benzodiazepine, such as flumazenil (f 1 umazen i 1), coronary arteries, peripheral and cerebral vasodilators; Substances acting on the central nervous system; hormones; sleeping pills; immunostatic preparations; muscle relaxants; prostaglandin; proteins; peptides; psychostimulants; sedatives and sedatives. A suitable active substance is further selected from, for example, parasympatholy t ic (such as East Test and Altopin), parasympathomie (parasympathomi me tic), acetamidine Biliary agents, (such as physost igmine, nicotine), neurol ept ic (such as chloropromazine, haloperidol), monoamine oxidase inhibition Agents, sympathomime tic (e.g. ephedrine, D-nor-pseudoephedrine, salbutamol, f enf luramine), sympatholytic agents and Antiparasympathetic agents (such as propranolol, timolol, bupranolol, cola

Page 15 200427464 V. Description of the invention (12) clonidine, dihydroergotamine), anxiolytics (such as diazepine, triazapine), local anesthetics (such as lidocaine) ), Central analgelsic, such as fentanyl, sufentanil, antirheumatic (such as' indomethacin,

Piroxicam, loronoxicam, coronary therapeutics (eg, nitroglycerin, isosorbide dinitrate), estrogen, gestagen, and males Androgen, antihistamines (eg, diphenhydramin, clestamin, terfenadin), prostaglandin derivatives, vitamins (eg, vitamin E, vitamin D3 (cho 1 eca 1 cif ero 1)), cytostatic agents (cytostatic ) Group of active substances with cardioactive glycosides such as digoxin and digit ox i η. The invention further relates to formulations which can be used in the form of a transmucosal or transdermal administration and which contain at least one matrix former and at least one pharmaceutically active agent. According to the invention, this formulation additionally contains at least one substance from the monoterpene group and at least one substance from the polyalcohol group, as shown above. 0. The medicament according to the invention can be advantageously used as Transdermal or transmucosal, do not administer active substances in the oral cavity, vagina or rectum. The drugs are used to treat or prevent human or animal diseases.

Page 16 200427464 V. Description of the invention (13) The present invention will be illustrated with the following formulation examples Water / ethanol (1 ·· 1, volume / volume) as a solvent 38% by weight 10% by weight 10% by weight 10 10% by weight 10% by weight 2% by weight

WalocelR CRT 30 (a) active substance (b) propylene glycol bovine vitamin B5 sorbitol flavor enhancer (a) sodium carboxymethyl cellulose; matrix former (b) detomidin Figure 1 shows the promoter system of the present invention ( Top line and top pillar) compared with control system (bottom line and bottom pillar) when applied in vivo (invivo). A particularly important implication is the fact that the sudden increase in the concentration of the active substance in the plasma occurred significantly earlier than in the control group because of an earlier activation effect.

Page 17 200427464 Schematic illustration Figure 1 shows the comparison of the accelerator system (top line and top pillar) of the present invention with a control system (bottom line and bottom pillar) when applied in vivo (i n v i v 〇). A particularly important implication is the fact that the sudden increase in the concentration of the active substance in the plasma occurred significantly earlier than in the control group because of an earlier activation effect.

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Claims (1)

200427464 6. Scope of patent application 1-A drug for transmucosal or transdermal administration of an active substance is characterized in that, in order to improve the absorption of the active substance, it contains at least one substance from the moter terpenes group, And at least one derived from polyalcohols is characterized by additionally containing vitamin 2 · The drug such as item 1 of the scope of patent application, biotin B5. 3. If the medicines in the scope of application for patents No. 1 or 2, the bean surname n li 嫦 group includes the following categories: 脂 Zhixing, /, Temple 仏 lies in the monoterpene fragrant mono ㈣, alcoholic single box of fat, Compounds, cyclic monoboxenes, dyneenes, monoterpenes with carbonyl groups, phenolic terpenes, phenolic monoterpenes that are more heterogeneous, and propylbenzene. Zao Tingxin, He Shengzi's transformation of early alkenes 4 4. As for the drug in any one of the scope of the patent application, Pentadol group contains the following substance categories and substances: $ (dihyMc) alcohol Alcohols, especially ethylene glycol, propylene glycol, butanol; alcohols of wet hydrogen, especially glycerol; higher-valent alcohols, especially polyalcohols. 5. If applied—please, is the drug in any one of the patent scope 1 to 4 characterized by menthol or other menthol containing? An olefinic mixture, and at least one polyol from the group comprising propylene glycol, butylene glycol, and ethylene glycol. 200427464 6. Scope of patent application 6 · If the scope of patent application is 1 to 5 items in the cup _ s — in the form of a mucosal administration, its characteristics are in ^ — $ see, preferably as a thin film transmucosal Pleasure form. Drugs such as those in the scope of patent application No. 6 are characterized by mucosal adhesions 8 · If the substances in the scope of patent application No. 6 are applied, Gandu ^ + Adhesive. The beam object 'is characterized by non-mucosal mucosa. 9. The drug in the scope of patent application No. 7 or 8 is characterized in that the film-like administration form is in an aqueous medium or a physiological liquid which can be degraded or degradable. 10. The medicine in the scope of patent claim 17 or 8 is characterized in that the film-like administration form is non-degradable in an aqueous medium or a physiological liquid. The medicament of any one is characterized by being formulated into an oral, vaginal or rectal administration form. 12. The drug according to any one of claims 1 to 5 in the scope of patent application, characterized in that it is expressed in the form of a transdermal administration, preferably as a transdermal therapeutic system. 200427464 13. The medicine basin according to any one of claims 6 to 12 of the scope of the application for patents:--solid matrix ', the matrix contains one or more matrix formers, to >-an active substance, and substance. The drug is characterized by its base adhesion. 14. If the quality of item 12 or 13 of the scope of patent application is mucosal adhesion or pressure on the skin, any one of the scope of the patent application mentioned above is used for the use of transmucosal single skin, especially oral, Descend i clan-style ancient times to win the ship ^, industrial leather fun medicine. 3 Μ tract or 疋 rectal active substance (class) 造 = preparation, film or percutaneous preparation preparation 16. The preparation contains at least one matrix formation and up to 522, 222, and 2 warfare agents , Which is characterized in that it additionally contains at least one substance from the group of medically active shellfish-polyols. Property 1 · If it is stated that the item 16 of the patent scope is necessary! There are provitamin b5. , I, "characterized by the additional containing = γ, such as the preparation of the patent application No. 16 or 17 of the preparation of the precocious alpine group contains' /, characterized by this class, aromatic army; κ pine phase fatty early Cyclic monoterpenoids, phenolic one-boxenes, mellow one-boxenes, one-box compounds with carbonyl groups, and propylbenzene. 200427464 Page 22