Percutaneous absorption preparation for relieving pain

Abstract

The present invention relates to a percutaneous absorption preparation for relieving pain and, more specifically, to a percutaneous absorption preparation having enhanced drug absorption efficacy. Every ingredient in the percutaneous absorption preparation according to the present invention is uniformly dispersed and does not aggregate, and thus a sufficient anti-inflammatory and pain-relieving efficacy of the drug can be continuously exhibited over a long period of time. In addition, the drug is percutaneously delivered in an amount sufficient for exhibiting efficacy while minimizing skin irritation, which is a disadvantage of percutaneous absorption preparations, and thus a high level of pain-relieving efficacy is exhibited. Moreover, skin penetration promotion in which a consistent amount of percutaneous drug absorption is sustained over a long period of time can be achieved, and thus side effects such as the hepatic first-pass effect in the body can be prevented.

Description

Transdermal analgesic

[0001] The present invention relates to a transdermal absorption preparation, and more particularly, to a transdermal absorption preparation for analgesia that enhances the absorption effect of a drug.

[0002] Pain is caused by noxious stimulation of nerve endings. Nociceptive pain is caused by noxious stimulation of acupoint receptors, such as from a needle prick or skin pinch, and transmits the stimulation to spinal neurons and the brain through nerve pathways. Neuropathic pain is caused by damage to nerve structures such as peripheral nerve endings or nociceptors, which become sensitive to stimulation and can produce stimulation without stimulation, such as the pain of herpes zoster after the rash has healed.

[0003] Approximately 70% of all cancer patients suffer from pain. Cancer-related pain is directly related to the primary and metastatic cancers that invade and compress organs, somatic cells, and nerve structures, as well as to treatment methods such as surgery, radiation therapy, or chemotherapy. Cancer pain is a combination of inflammatory, neuropathic, and ischemic mechanisms, affecting one or more areas.

[0004] As a flexible model for cancer pain management, the WHO proposes a three-tiered approach: Tier 1 (non-opioid analgesics, such as paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs)) for mild pain, Tier 2 (weak opioids, such as codeine or dextropropoxyphene) for mild to moderate pain, and Tier 3 (strong opioids, such as morphine) for moderate to severe pain. Opioids used to treat mild to moderate pain include codeine (8%), tramadol (8%), dextropropoxyphene (5%), and dihydrocodeine (2%). For moderate to severe pain, morphine is most commonly used, administered orally in 40% of cases and parenterally in 10%, followed by fentanyl patches (14%), oxycodone (4%), methadone (2%), and hydromorphone (1%).

[0005] With the development of various new treatment methods and improved survival rates for cancer patients, the rate of long-term opioid use for pain management is also increasing. Consequently, in addition to known side effects, new adverse effects are emerging, such as tolerance to analgesic effects, dependence and addiction, hypogonadism, osteoporosis, immunosuppression, cognitive dysfunction, and opioid-induced hyperalgesia (OIH), which inevitably accompany continued dose increases.

[0006] To overcome these opioid side effects, combination therapy with low-dose opioids and adjuvants such as antidepressants (amitriptyline, duloxetine, venlafaxine, etc.) or antiepileptic drugs (gabapentin, pregabalin) is recommended. Antidepressants work by altering the bioavailability of supraspinal serotonin (5-HT) and norepinephrine (NA), inhibiting amine reuptake and transmitting bulbar inhibitory signals. These mechanisms have been reported to be effective in treating various pain conditions, including cancer. For example, amitriptyline, although developed as an antidepressant, is frequently recommended as a first-line treatment for fibromyalgia, chronic musculoskeletal pain, migraine, and neuropathic pain. Accordingly, it has been reported that desirable effects are achieved when opioids such as tramadol, tapentadol, and methadone are used in combination with antidepressants such as amitriptyline, loxetine, and venlafaxine.

[0007] To overcome the side effects of opioids, non-opioid medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are also commonly used. Oral administration is the primary route of administration for NSAIDs, and they are widely used due to their excellent anti-inflammatory and analgesic effects and relatively minimal side effects. However, long-term use or overdose is known to cause adverse effects such as hepatic or gastrointestinal disturbances. Furthermore, oral administration, due to the first-pass hepatic effect, reduces bioavailability, necessitating multiple doses. Therefore, there is a significant need to improve this drawback. Furthermore, while NSAIDs are effective for acute pain and arthritis, they are less effective for moderate to severe pain, such as chronic pain, cancer pain, and neuropathic pain. Therefore, narcotic analgesics such as fentanyl, buprenorphine, and morphine are commonly used for moderate to severe pain.

[0008] While narcotic analgesics are effective in relieving pain, they can cause side effects such as dizziness, somnolence, edema, peripheral edema, vasodilation, dyspnea, constipation, dry mouth, nausea, vomiting, and headache, so caution is advised when using them. For these reasons, narcotic analgesics are primarily administered in a way that maintains a constant blood drug level, and transdermal preparations are considered the most suitable formulation. However, the large molecular weight of most narcotic analgesics, including buprenorphine, makes transdermal absorption difficult, which is a drawback.

[0009] There is growing interest in research and development of medications that address the shortcomings of narcotic analgesics while also being effective in treating moderate to severe pain. Active research is underway on increasing the dosage of nonsteroidal anti-inflammatory drugs (NSAIDs) or combining NSAIDs with medications effective in pain management. As a result, a combination formulation of acetaminophen and tramadol has been commercialized and is now available.

[0010] However, due to limitations such as the instability of the formulation and low skin penetration of compounded preparations, moderate-intensity pain medications have been developed only as oral or injectable agents. Systemic treatments administered orally or intravenously cause serious side effects such as dizziness, drowsiness, amnesia, dry mouth, or even urinary retention and nausea, leading to poor compliance and unsatisfactory pain control. Amitriptyline, an antidepressant used as an adjunct to pain management, is also administered orally. The onset of action of oral amitriptyline is slow (requiring 5 to 7 days of treatment to begin to perceive its effects), varies from patient to patient, is unstable, and causes side effects such as hypotension, tachycardia, dry mouth, and blurred vision.

[0011] Accordingly, the development of transdermal medications is actively underway to improve the inconvenience of oral or injectable medications and enable patients to use them more comfortably. As a result, gels and liquids containing various analgesics have been developed and commercialized. However, gels and liquids are applied directly to the skin without a drug protective layer to seal the effective drug, which causes the user's clothing to get dirty, the amount applied per application is inconsistent, and the inconvenience of having to apply multiple times a day. In addition, there is the problem of low bioavailability due to low skin permeability.

[0012] To improve the problems of these gel and liquid formulations, transdermal absorption preparations including wet compresses and plasters have been developed. Not only does the amount applied remain constant when applied, but the inconvenience of administering medication, such as the drug getting on clothing or having to be applied multiple times a day, has been improved. Plaster formulations can be easily applied to any part of the body depending on the material of the fabric used and the properties of the adhesive ingredient. However, there are limitations in that in order to increase the skin permeability of the drug, crystals must not be precipitated within the formulation, the drug must be maintained at a saturation concentration as much as possible while maintaining the properties of the formulation, and an appropriate skin penetrant must be used to increase the amount of drug distributed and diffused into the stratum corneum.

[0013] Transdermal drug delivery systems release drugs into the patient's skin when applied to the patient's skin, translocating through multiple layers to exert their effects. Methods for promoting drug absorption through the skin include physical, biochemical, and chemical methods. Physical methods primarily utilize heat, electricity, and ultrasound energy, while biochemical methods primarily utilize prodrugation. Chemical methods primarily utilize complex formation, various substances, surfactants, solvents, and fatty acids, and are the most widely used. The mechanism of enhanced skin penetration lies in altering the thermodynamic properties of the drug or changes in the properties of the skin. In particular, changes in the fluidity of lipid components within the skin and interactions with sugars and proteins within skin cells promote drug distribution into the stratum corneum.

[0014] Among the various methods for promoting skin penetration of such drugs, the use of skin penetration enhancers is the most common. However, when a patient's condition is chronic and the drug is administered frequently, itching, erythema, and skin rashes occur more frequently. Primary irritation and sensitization to the skin thus pose significant limitations in drug application, with 20-30% of currently marketed formulations exhibiting adverse skin reactions.

[0015] Therefore, skin penetration enhancers must be nontoxic and non-irritating, not cause physiological side effects, and be compatible with the drug and the adhesives and excipients that make up the transdermal preparation. Furthermore, the skin penetration enhancer must be present in the formulation in an amount that maintains its effect throughout the transdermal preparation's application time. However, none of the skin penetration enhancers currently in development or commercialization satisfies these requirements.

[0016] For the reasons mentioned above, there has been a growing interest in complex gel preparations for pain treatment that combine the anti-inflammatory and analgesic effects of nonsteroidal anti-inflammatory drugs, the immediate pain relief of local anesthetics, and the neuropathic pain treatment effect of amitriptyline.

[0017] Against this backdrop, the inventors of the present invention have been researching for a long time a transdermal analgesic preparation that can solve the problems of the formulation of existing pain suppressants and replace or exclude conventional skin penetration enhancers.

[0018] As a result, even with a simpler configuration such as not using a skin penetration enhancer, the transdermal penetration efficiency of an effective drug can be improved, thereby reducing the amount of injected drug required for the expression of appropriate drug effects. In addition, by maintaining a constant amount of transdermal absorption of the drug for a long time with only a small amount of drug through high skin permeability, the first-pass effect of the liver can be avoided, thereby preventing side effects in the body. In addition, the side effects of skin irritation due to skin contact of the drug can be alleviated, and a transdermal absorption preparation that has sufficient adhesiveness and detachability for attachment to the skin and is easy to manufacture has been completed.

[0019] Each description and embodiment disclosed in this invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention is not limited by the specific descriptions described below.

[0020] Additionally, terms not specifically defined herein should be understood to have the meanings commonly used in the technical field to which the present invention pertains. Furthermore, unless specifically defined in context, the singular includes the plural, and vice versa.

[0021] One aspect of the present invention provides a transdermal absorption preparation comprising a) a support layer and b) a matrix layer, wherein the matrix layer comprises (i) an active drug, (ii) an adhesive agent, (iii) a tackifying resin, and (iv) a plasticizer.

[0022] The a) support layer constituting the transdermal absorption preparation according to the present invention increases the storage and stability of the effective drug contained in the b) matrix layer, and serves to facilitate the application of the drug to all parts of the body.

[0023] The above-mentioned support layer can be easily attached to the skin, can prevent drug loss due to drug stability during storage, does not react with the skin and does not cause an allergic reaction, can attach a drug layer, and has self-shape retention, and there are no particular limitations on its material or shape, and any material used in conventional transdermal absorption preparations may be used. For example, the support layer may be a permeable or impermeable material including a polymer film such as polyester, polyolefin, polyurethane, polyvinyl acetate, polyvinylidene chloride, polyethylene, ethylene vinyl acetate, polyethylene terephthalate, polybutylene terephthalate, coated paper, aluminum sheet, cellulose ester, etc., a fabric, knitted fabric, nonwoven fabric, and paper made of fibers such as polyamide, or a laminate made of a combination of two or more of these using a porous membrane. In the present invention, a laminated form of an ethylene vinyl acetate film and a polyester film having a thickness of 15 to 50 ㎛ can be used, but is not limited thereto.

[0024] The above b) matrix layer constituting the transdermal absorption preparation according to the present invention comprises (i) an effective drug exhibiting an analgesic effect, (ii) an adhesive agent, (iii) an adhesive-imparting resin, and (iv) a plasticizer, in order to support or include the effective drug. In this way, even though the effective drug and the adhesive (adhesive agent and adhesive-imparting resin) are composed of a single adhesive layer, the effective drug does not crystallize within the preparation, but maintains a saturated concentration within a range that maintains the properties of the preparation, and the drug does not interact with the adhesive, so that the drug easily permeates and diffuses through the skin, and all components such as the drug and the adhesive present in the preparation are uniformly dispersed without agglomeration, and at the same time, the matrix layer can have sufficient adhesive strength to adhere to the skin. Therefore, the transdermal absorption preparation of the present invention does not require a complicated manufacturing process.

[0025] The content of the above (i) effective drug may be 5 to 20 wt% based on the total weight of the b) matrix layer, and within the above range, the properties of the transdermal absorption preparation may be maintained while the drug may be included at a saturated concentration. In addition, the content of the effective drug may be 0.5 mg / cm2 or more and less than 1.5 mg / cm2 per unit area of ​​the matrix layer. If the content of the effective drug is included to be less than 0.5 mg / cm2, the amount of drug permeated through the skin may decrease, making it difficult to obtain effective efficacy. If the content of the effective drug is included to be 1.5 mg / cm2 or more, the cohesive force of the polymer adhesive, which is the matrix layer base, may decrease due to the drug, and may cause adverse effects such as skin irritation due to the drug.

[0026] The above effective drugs may include, for example, non-steroidal anti-inflammatory drugs, analgesics, local anesthetics, antidepressants, or combinations thereof, but there is no limitation as long as they can exhibit an analgesic effect.

[0027] In the present invention, the non-steroidal anti-inflammatory agent may be included in an amount of 0.1 to 30 wt% of the total composition of the transdermal absorption preparation. If the non-steroidal anti-inflammatory agent is included in an amount less than the above range, the desired pain suppression or reduction effect will not be exhibited, and if the non-steroidal anti-inflammatory agent is included in an amount exceeding the above range, no further effect can be expected, and since the non-steroidal anti-inflammatory agent cannot exist in a stable dissolved state in the preparation and is precipitated in a crystal state, side effects such as decreased penetration effect, decreased adhesiveness, and skin irritation may occur. The non-steroidal anti-inflammatory agent used in the present invention may have a ring structure, and specifically, may be indomethacin, ketoprofen, flurbiprofen, felbinac, piroxicam, ketorolac, loxoprofen, diclofenac, mefenamic acid, salicylic acid, a pharmaceutically acceptable salt thereof, or a combination thereof, but is not limited thereto.

[0028] In the present invention, the analgesic may be included in an amount of 0.1 to 30 wt% of the total composition of the transdermal absorption preparation. If the analgesic is included in an amount less than the above range, the desired pain suppression or reduction effect will not be exhibited, and if the analgesic is included in an amount exceeding the above range, no further effect can be expected, and since it cannot exist in a stable dissolved state in the preparation but precipitates in a crystal state, side effects such as reduced penetration effect, reduced adhesiveness, and skin irritation may occur. Examples of the analgesic used in the present invention may include, but are not limited to, tramadol, buprenorphine, acetaminophen, ibuprofen, pharmaceutically acceptable salts thereof, or combinations thereof.

[0029] In the present invention, the local anesthetic may be included in an amount of 1 to 20 wt% of the total composition of the transdermal absorption preparation. If the local anesthetic is included in an amount less than the above range, the desired pain suppression or reduction effect will not be achieved, and if the local anesthetic is included in an amount exceeding the above range, a therapeutic effect greater than the above cannot be expected, and since it cannot exist in a stable dissolved state in the preparation but precipitates in a crystal state, side effects such as reduced penetration effect, reduced adhesiveness, and skin irritation may occur. Examples of the local anesthetic used in the present invention may include, but are not limited to, ester-type procaine, chloroprocaine, and tetracaine; amide-type prilocaine, lidocaine, mepivacaine, bupivacaine, ropivacaine, and etidocaine, pharmaceutically acceptable salts thereof, or combinations thereof.

[0030] It is preferable to include a non-steroidal anti-inflammatory drug or analgesic and a local anesthetic in the matrix layer according to the present invention in a molar ratio of 1:0.1 to 3. If included in a ratio other than the above ratio, the non-steroidal anti-inflammatory drug or analgesic and the local anesthetic remain in a crystalline state in the transdermal absorption preparation, resulting in side effects such as reduced penetration effect, decreased adhesiveness, and skin irritation.

[0031] In the present invention, the antidepressant may be included in an amount of 0.1 to 10 wt% of the total composition of the transdermal absorption preparation. If the antidepressant is included in an amount less than the above range, the desired pain suppression or reduction effect will not be achieved, and if the antidepressant is included in an amount exceeding the above range, no further therapeutic effect can be expected. In addition, since the antidepressant cannot exist in a stable dissolved state within the preparation but precipitates in a crystal state, side effects such as reduced penetration effect, reduced adhesiveness, and skin irritation may occur. Examples of antidepressants used in the present invention may be norepinephrine-reuptake inhibitors (NRls), selective serotonin-reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin and noradrenaline-reuptake inhibitors ("SNRls), corticotropin-releasing factor (CRF) antagonists, alpha-adrenoceptor antagonists, NCl-receptor antagonists, 5-HT1A-receptor agonists, 5-HT1A-receptor antagonists, 5-HT1A-receptor partial agonists, atypical antidepressants, other antidepressants, etc. In addition, the antidepressants include all pharmaceutically acceptable salts, all complexes and all prodrugs of antidepressants.

[0032] Examples of the above norepinephrine-reuptake inhibitors include amitriptyline, desmethylamitriptyline, climipramine, doxepin, imipramine, imipramine-oxide, trimipramine, adinazolam, amitriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, buttriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepine, fluacizine, Examples thereof include, but are not limited to, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, tianeptine, and pharmaceutically acceptable salts thereof.

[0033] Examples of the above serotonin-reuptake inhibitors include, but are not limited to, binedaline, m-chloropiperzine, citalopram, duloxetine, etoperidone, femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, nefazodone, oxaflazone, paroxetine, prolintane, ritaserin, sertraline, tandosporone, venlafaxine, and zimeldine, and pharmaceutically acceptable salts thereof.

[0034] Among the above monoamine-oxidase inhibitors, examples of non-selective monoamine oxidase inhibitors include, but are not limited to, amiflamine, vanoxerine (boxeprazine), AGN 2253 (Nicholas Kiwi), iproniazid, isocarboxazid, M-3-PPC (Draxis), nialamid, phenelzine, pargyline, and tranylcypromine, and pharmaceutically acceptable salts thereof.

[0035] Examples of selective monoamine oxidase inhibitors include clorzyrine, shimokisatone, befloxatone, brosaformine, bazinaprine, BW-616 U (Burroughs Elcom), BW-1370 U87 (Burroughs Elcom), CS-722 (RS-722) (Sankyo), E-2011 (Eisai), harmine, harmaline, moclobemide, PharmaProjects 3975 (Hoechst), RO 41-1049 (Roche), RS-8359 10 (Sankyo), T-794 (Tanabe Pharmaceutical), troxatone, KY 1349 (Kalir and Youdim), LY-51641 (Lilly), LY-121768 (Lilly), M&B 9303 (May and Baker), MDL 72394 (Marion Merrell), MDL 72392 (Marion Merrell), sercloremine, and MO 1671, and pharmaceutically acceptable salts thereof, but are not limited thereto.

[0036] Examples of the above serotonin and norepinephrine reuptake inhibitors include, but are not limited to, mirtazapine, venlafaxine, and pharmaceutically acceptable salts thereof.

[0037] The above corticotropin-releasing factor antagonists include compounds that, when systemically administered to a mammal, act as corticotropin antagonists or display receptor-binding properties or properties associated with CRF antagonists when tested in a standard assay either in vivo or in vitro.

[0038] Examples of the above alpha-adrenoreceptor antagonists include, but are not limited to, phentolamine and pharmaceutically acceptable salts thereof.

[0039] The above NK1 receptor antagonists include compounds that act as NK1 receptor antagonists (Neurokinin 1 substance P receptor antagonists) when systemically administered to a mammal or act as NK1 receptor antagonists when tested in a standard assay in vivo or in vitro.

[0040] Examples of the above 5-HT1A-receptor agonists, antagonists, and partial agonists include, but are not limited to, buspirone, flesinoxan, gepirone, ipsapirone, and pharmaceutically acceptable salts thereof.

[0041] Examples of the above atypical antidepressants include, but are not limited to, bupropion, dimethazan, fencamine, fenpentadiol, levophacetoperance, metralindone, mianserin, cotinine, rolicyprine, rolipram, nefopam, lithium, trazodone, viloxazine, sibutramine, and pharmaceutically acceptable salts thereof.

[0042] In a specific embodiment of the present invention, the antidepressant may be a tricyclic antidepressant (TCA). The term "tricyclic antidepressant" as used herein refers to a drug having a chemical structure containing three ring structures and mainly used as an antidepressant. Specifically, the tricyclic antidepressant may be, but is not limited to, imipramine, desipramine, clomipramine, lofepramine, amitriptyline, nortriptyline, protriptyline, buttriptyline, dibenzoxepin (doxepin), dibenzothiepin (dosulepine), dibenzoxazepine (amoxapine), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0043] The content of the above (ii) adhesive agent may be 15 to 35 wt% based on the total weight of the b) matrix layer. Within the above range, sufficient permeability of the effective drug and sufficient cohesiveness as an adhesive preparation can be maintained.

[0044] In a specific embodiment of the present invention, when ketoprofen, diclofenac sodium, tramadol, lidocaine or amitriptyline is used as the effective drug, the adhesive base may be a styrene-isoprene-styrene block copolymer (SIS). Ketoprofen, lidocaine and amitriptyline are composed of molecules having a ring structure. Therefore, when ketoprofen, lidocaine and amitriptyline are used as the effective drug included in the b) matrix layer, the functional groups of these drugs may interact with other functional groups present in the adhesive and precipitate as crystals in the formulation, which may act as a factor interfering with the diffusion and penetration process of the drug in the adhesive through the skin and may reduce the transdermal absorption rate of the drug.

[0045] In this regard, in the examples of the present invention described below, the cumulative permeation amount (㎍ / ㎠), the cumulative permeation amount (%) compared to the initial content, and the skin permeation rate (㎍ / ㎠ / h) of the effective drug after 24 hours were evaluated using various adhesive bases belonging to the acrylic (Durotak 2052), synthetic rubber (polyisobutylene), or natural rubber. As a result, it was confirmed that b) when a styrene-isoprene-styrene block copolymer was used as the adhesive base in the matrix layer, the transdermal permeation efficiency of the effective drug was significantly superior. This is understood to be because the styrene-isoprene-styrene block copolymer is an adhesive base capable of minimizing interaction with the drug.

[0046] Therefore, when a styrene-isoprene-styrene block copolymer is used as an adhesive base, the effective drug can be maintained at a saturated concentration within a range that maintains the properties of the formulation, and even with a small amount of the effective drug, a sufficient amount of the drug to produce the desired effect can be transdermally administered, and further, skin irritation can be alleviated by reducing the amount of drug used. In particular, the transdermal absorption preparation according to the present invention can achieve high skin permeability of the drug even when the amount of a skin penetration enhancer used is minimized or not used, and thus side effects such as skin irritation caused by the use of a transdermal absorption enhancer can be alleviated.

[0047] The content of the above (iii) tackifying resin may be 25 to 50 wt% based on the total weight of the b) matrix layer, and within the above range, sufficient adhesiveness and cohesiveness as a transdermal absorption preparation can be maintained. The tackifying resin may be a natural resin, a synthetic resin, or a mixture thereof, specifically, an alicyclic hydrocarbon resin, for example, a styrene alpha methyl styrene resin (e.g., Crystalex F85); an aliphatic hydrocarbon resin (e.g., Escorez 1401); a hydrogenated hydrocarbon resin (e.g., Regalite R1100); Rosin derivatives such as rosin resins, for example, rosin, hydrogenated rosin, or esters thereof, for example, glycerol esters of rosin, glycerol esters of hydrogenated rosin, pentaerythritol esters of rosin, etc. (e.g., KE311); terpene resins, and polyester resins, for example, maleic acid resins, but are not limited thereto. Preferably, one or more of the terpene resins and rosin ester resins may be mixed and used.

[0048] In this regard, in the examples of the present invention described below, the cumulative permeation amount (㎍ / ㎠), the cumulative permeation amount (%) compared to the initial content, and the skin permeation rate (㎍ / ㎠ / h) of the effective drug after 24 hours were evaluated using various adhesive bases belonging to alicyclic hydrocarbon resins, aliphatic hydrocarbon resins, rosin-based resins, and terpene resins. As a result, b) it was confirmed that the transdermal permeation efficiency of the effective drug was remarkably excellent when rosin-based resins and terpene resins were used as adhesive-imparting resins in the matrix layer.

[0049] Therefore, when rosin resin and / or terpene resin is used as the adhesive resin, the effective drug can be maintained at a saturated concentration within a range that maintains the properties of the formulation, and even if a small amount of the effective drug is used, a sufficient amount of the drug to produce the desired effect can be transdermally administered, and further, skin irritation can be alleviated by reducing the amount of drug used. In particular, since the transdermal absorption preparation according to the present invention can achieve high skin permeability of the drug even when the amount of a skin penetration enhancer used is minimized or not used, side effects such as skin irritation caused by the use of a transdermal absorption enhancer can be alleviated.

[0050] The content of the above (iv) plasticizer may be 5 to 20 wt% based on the total weight of the b) matrix layer, and within the above range, sufficient adhesiveness and cohesiveness as a transdermal absorption agent can be maintained. The above plasticizer may be selected from the group consisting of petroleum oil (e.g., paraffin process oil, liquid paraffin, naphthenic process oil, aromatic process oil, etc.); squalane; squalene; plant oil (e.g., olive oil, camellia oil, castor oil, tall oil, peanut oil); synthetic oil (silicon oil); Dibasic acid esters (e.g., dibutyl phthalate, dioctyl phthalate, etc.); liquid rubber (e.g., polybutene; liquid isoprene rubber, etc.); liquid fatty acid esters (e.g., isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, etc.); diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; clotamiton; caprylpyrrolidone; Laurylpyrrolidone or mixtures thereof may be used, but are not limited thereto.

[0051] In a specific embodiment of the present invention, the b) matrix layer comprises (i) an effective drug, (ii) an adhesive agent, (iii) an adhesive-imparting resin, and (iv) a plasticizer in a weight ratio of 1 to 1.5: 1.5 to 3: 4 to 5: 0.5 to 2. Within this range of combination ratios, the transdermal absorption preparation can control the skin permeability of the effective drug to a certain level, improve the skin permeation amount and skin permeation rate of the effective drug, promote drug release into the skin, and maintain adhesiveness without crystallization even during long-term storage. On the other hand, when the range of combination ratios is exceeded, the skin permeation effect of the effective drug of the transdermal absorption preparation may be reduced, and problems such as deterioration of physical properties such as precipitation of the effective drug as crystals and deterioration of the adhesiveness of the preparation may occur.

[0052] The transdermal absorption preparation of the present invention can sufficiently achieve the effects intended by the present invention even if it contains only (i) an active drug, (ii) an adhesive agent, (iii) an adhesive-imparting resin, and (iv) a plasticizer. Specifically, the transdermal absorption preparation of the present invention can exhibit sufficient efficacy even with an amount less than 1.5 mg / cm2, preferably 0.5 mg / cm2 or more and less than 1.5 mg / cm2, more preferably 0.8 mg / cm2 or more and 1.2 mg / cm2 or less, for example, with a content of 0.8 mg / cm2, even without adding any other additives other than (i), (ii), (iii), and (iv). That is, it is possible to achieve an effect in which the 24-hour release amount of the drug is 12 to 20 mg, the 12-hour cumulative permeation amount of the drug is 30 wt% or more of the initial content, for example, 30 wt% or more and 60 wt% or less, and the skin permeation rate of the drug is more than 18 ㎍ / ㎠ / h, particularly 20 ㎍ / ㎠ / h or more, and more particularly 20 ㎍ / ㎠ / h or more and 30 ㎍ / ㎠ / h or less.

[0053] Additionally, the transdermal absorption preparation of the present invention may not include a skin penetration enhancer. Specifically, the transdermal absorption preparation of the present invention may exhibit a high skin penetration rate and a high cumulative permeation amount of the effective drug even without including a skin penetration enhancer such as isopropyl myristate or sorbitan monooleate.

[0054] b) The matrix layer according to the present invention may optionally further include one or more selected from the group consisting of skin penetration enhancers, UV blockers, and antioxidants commonly used in the field of transdermal absorption preparations, for the purpose of further improving compatibility with drugs and other excipients, formulation stability, etc., as needed. However, the addition of the transdermal absorption enhancers, UV blockers, or antioxidants is not essential, and as mentioned above, the transdermal absorption preparation of the present invention can exhibit sufficient efficacy and high skin permeability even without the addition of these.

[0055] As the above-mentioned sunscreen, a liquid organic sunscreen having an ultraviolet ray absorption effect can be used. For example, ethylhexyl methoxycinnamate, isoamyl p-methoxycinnamate, bis-ethylhexyloxyphenol methoxyphenyl triazine, C12-15 alkyl benzoate, titanium oxide, aluminum stearate, polyhydroxystearic acid, alumina, and ethylhexyl salicylate can be mentioned, and in addition, organic ultraviolet ray absorbers having an ultraviolet ray absorption effect can be used, such as oxybenzone, octocrylene, diethylhexylbutamidotriazone, 4-methylbenzylidenecamphor, 3-benzylidenecamphor, octyldimethyl PABA, anisotriazine, and polysilicon, but are not limited thereto. In addition, the UV blocker used in the present invention may be an inorganic UV blocker such as a solid powder UV filter, and a specific example thereof may include titanium oxide, and other examples may include zinc oxide, etc. The UV blocker may be used by adjusting its content depending on the desired UV blocking effect.

[0056] As the antioxidant, compounds, derivatives, and salts thereof having antioxidant activity can be used. For example, one or more selected from the group consisting of phenolic antioxidants (e.g., tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), triethylene glycol bis(3-tert-butyl-4-hydroxy-5-methylphenyl)propionate, bis-(2.4-di-tert-butyl-phenyl phosphate), octadecyl 3,5-di-(tert)-butyl-4-hydroxyhydrocinnamate, 2,4-bis(dodecylthiomethyl)-6-methylphenol, etc.); ascorbyl stearate; alpha-lipoic acid; glutathione; coenzyme Q10; gamma-linolenic acid; and linoleic acid can be used, but is not limited thereto.

[0057] In addition, the transdermal absorption preparation according to the present invention may further include c) a peeling layer. The peeling layer may be a release film or a laminate thereof commonly used in transdermal absorption preparations. For example, a film, paper, or a laminate thereof made of polyethylene, polyester, polyvinyl chloride, or polyvinylidene chloride coated with a silicone resin or a fluororesin may be used.

[0058] In addition, the transdermal absorption preparation according to the present invention may not include a separate intermediate layer or an adhesive layer including a silicone adhesive or the like, in addition to a) the support layer and b) the matrix layer.

[0059] The transdermal absorption preparation according to the present invention may be a patch, a wet compress, or a plaster.

[0060] The transdermal absorption preparation according to the present invention has a 24-hour cumulative permeation amount of the effective drug or a pharmaceutically acceptable salt thereof of 30 wt% or more of the initial content, for example, 30 wt% or more and 60 wt% or less.

[0061] In addition, the transdermal absorption preparation according to the present invention has a 24-hour release amount of 12 to 20 mg of the active drug ingredient or a pharmaceutically acceptable salt thereof.

[0062] In addition, the transdermal absorption preparation according to the present invention has a skin penetration rate of the active drug ingredient or a pharmaceutically acceptable salt thereof of more than 3 ㎍ / ㎠ / h, for example, 3 ㎍ / ㎠ / h or more, for example, 3 ㎍ / ㎠ / h or more and 7 ㎍ / ㎠ / h or less.

[0063] Accordingly, the present invention can also provide a transdermal absorption preparation containing an effective drug ingredient or a pharmaceutically acceptable salt thereof in an amount of 0.5 mg / cm2 or more and less than 1.5 mg / cm2, for example, 0.5 mg / cm2 or more and 1.2 mg / cm2 or less, for example, 0.8 mg / cm2, and having a 24-hour release amount of the drug of 5.5 to 11.0 mg.

[0064] The transdermal absorption preparation according to the present invention exhibits little or no skin irritation, unlike conventional preparations that exhibited skin irritation. The primary skin irritation index (PII) according to Draize's skin reaction evaluation table (Draize's criteria: 1959) is preferably 0.3 or less, more preferably 0.25 or less, and even more preferably 0.2 or less.

[0065] The transdermal absorption preparation according to the present invention has all components in the preparation uniformly dispersed without aggregation, so that sufficient anti-inflammatory and analgesic effects can be continuously obtained for a long period of time.

[0066] In addition, it can minimize skin irritation, which is a disadvantage of transdermal preparations, while delivering a sufficient amount of drug to the skin to exhibit the drug effect, thereby exhibiting a high analgesic effect, and can achieve skin penetration promotion that maintains the drug's percutaneous absorption at a constant amount for a long time, thereby preventing side effects in the body such as the first-pass effect.

[0067] In addition, the transdermal absorption preparation of the present invention is very advantageous in that it can be manufactured through a simple manufacturing process that does not form a separate adhesive layer including a silicone adhesive or the like.

[0068] Figure 1 shows a cross-sectional view of a percutaneous absorption preparation according to the present invention. Here, A represents a support layer, B represents a matrix layer, and C represents a peeling layer.

[0069] Figures 2 to 4 are graphs showing the amount of drug remaining after skin application of ketoprofen, one of the transdermal absorption preparations according to the present invention.

[0070] Figure 5 is a graph showing the amount of drug remaining after skin application of diclofenac sodium (Diclofenac Na), a percutaneous absorption preparation according to the present invention.

[0071] Figure 6 is a graph showing the amount of drug remaining after skin application of tramadol, one of the transdermal absorption preparations according to the present invention.

[0072] Figure 7 is a graph showing the amount of drug remaining after skin application of lidocaine, one of the transdermal absorption preparations according to the present invention.

[0073] Figure 8 is a graph showing the amount of drug remaining after skin application of amitriptyline, one of the transdermal absorption preparations according to the present invention.

[0074] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are provided only to specifically illustrate the present invention, and the scope of the present invention is not limited to these examples and experimental examples.

[0075] Examples 1 to 5. Preparation of transdermal absorption preparations

[0076] An adhesive solution was prepared using a styrene-isoprene-styrene block copolymer (hereinafter referred to as SIS) as a drug-containing matrix, liquid paraffin (Sonneborn, Kaydol) as a plasticizer, and a terpene resin (Kraton, TP7042) and a rosin ester resin (Kraton, Sylvalite 9000) as a tackifier.

[0077] The effective drug was added to the adhesive solution thus prepared and mixed uniformly. Subsequently, the drug-containing adhesive solution was formed into a sheet on a polyester release film with the thickness indicated in Table 1. This was laminated to a support layer and cut to a consistent size.

[0078] As a result, a transdermal absorption preparation containing a non-steroidal anti-inflammatory drug, a local anesthetic, and a tricyclic antidepressant was prepared, which was used as a sample in Examples 1 to 5.

[0079] Example 1 Example 2 Example 3 Example 4 Example 5 Unit: mg Dosage Dosage Dosage Dosage Dosage Effective Drug Ketoprofen 5.00--5.005.00 Diclofenac sodium 5.00---Tramadol 5.00---Lidocaine 3.003.003.003.003.003.00 Amitriptyline 3.003.003.003.003.00 Adhesive base SIS (Styrene-Isoprene-Styrene block copolymer) 22.0022.0022.0018.0026.00 NR (Natural Rubber)-----SBS (Styrene Butadiene Styrene block copolymer)-----SEP (Styrene-ethylene-propylene-styrene Copolymer)-----Polyisobutylene-----Durotak 2052-----Adhesive ResinAliphatic Hydrocarbon Resin-----Alicyclic Hydrocarbon Resin-----Terpene Resin 17.0017.0017.0019.0015.00Rosin Ester Resin 27.0027.0027.0029.0025.00ExcipientTitanium Oxide 2.002.002.002.002.00Butyl Hydroxytoluene 1.001. 001.001.001.00PlasticizerLiquid paraffin12.0012.0012.0012.0012.00Skin penetration enhancerIsopropyl myristate-----Sorbitan monooleate-----SolubilizerN-Methyl-2-pyrrolidone4.004.004.004.004.00Caprylaulate4.004.004.004.004.00Total100.0100.0100.0100.0100.0

[0080] Comparative Examples 1 to 12. Preparation of comparative samples of transdermal absorption preparations

[0081] In order to compare the effects with the transdermal absorption preparations manufactured in Examples 1 to 5, the components and content of the effective drug contained in the matrix layer, the type of adhesive, the presence or absence of an adhesive-imparting resin, the presence or absence of a plasticizer, and the presence or absence of a skin penetration promoter were changed as shown in Table 2 below, and transdermal absorption preparations were manufactured in the same manner as in Examples 1 to 5 in all other respects. These were used as samples of Comparative Examples 1 to 12.

[0082] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Unit: mg Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Dosage Active Drug Ketoprofen 5.00 5.00 11.00 -- 5.00 5.00 5.00 5.00 5.00 5.00 5.00 11.00 Diclofenac sodium --- 11.00 ------ Tramadol --- 11.00 ------ Lidocaine 3.00 3.00 --- 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 Amitriptyline 3.00 3.00 --- 3.00 3.00 3.00 3.00 3.00 3.00 Adhesive base SIS --- 22.0 022.0022.00---22.0022.0022.0022.00NR-----22.00------SBS------22.00-----SEP-------22.00----Polyisobutylene-22.00----------Durotak205271.00-----------Adhesion-imparting resinAliphatic hydrocarbon resin--------17.00---Alicyclic hydrocarbon resin---------17.00--Terpene resin-12.0012.0012.0012.0017.0017.0017.00- -12.0014.00Rosin ester resin-22.0022.0022.0022.0027.0027.0027.0027.0027.0022.0024.00ExcipientTitanium oxide-2.002.002.002.002.002.002.002.002.002.002.002.002.002.002.00Butylhydroxytoluene-1.001.001.001.001.001.001.001.001.001.001.001.00PlasticizerLiquid paraffin-12.0012.0012.0012.0012.0012.0012.0012.0012.0012.0012.0012.001 2.0012.00 Skin penetration enhancer Isopropyl myristate 5.005.005.005.005.00-----5.00-Sorbitan monooleate 5.005.005.005.005.00-----5.00-Solubilizer N-Methyl-2-pyrrolidone 4.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.004.00Total 100.0100.0100.0100.0100.0100.0100.0100.0100.0100.0100.0100.0100.0100.0.

[0083] Comparative Examples 13 to 17. Preparation of comparative samples of transdermal absorption preparations

[0084] In order to compare the effects with the transdermal absorption preparation of Example 4, the ratios of the adhesive agent, adhesive-providing resin, and plasticizer included in the matrix layer were changed as shown in Table 3, and other methods were the same as in Examples 1 to 5 to manufacture the transdermal absorption preparation. These were used as samples of Comparative Examples 13 to 17.

[0085] Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 Unit: mg Dosage Dosage Dosage Dosage Dosage Active ingredient Ketoprofen 5.5 6 5.2 9 5.4 4 5.2 6 5.5 9 Diclofenac Sodium-----Tramadol-----Lidocaine 3.343.173.273.153.35Amitriptyline 3.343.173.273.153.35Adhesive base SIS 18.3517.4619.5918.9318.44NR-----SBS-----SEP-----Polyisobutylene-----Durotac 2052-----Adhesion imparting resin Aliphatic hydrocarbon resin-----Alicyclic hydrocarbon resin-----Terpene resin 20.6522.5020.4422.5020.44Rosin ester resin 20.6522.5020.442 2.5020.44 Excipients Titanium oxide 2.222.122.182.102.24 Butylhydroxytoluene 1.111.061.091.051.12 Plasticizer Liquid paraffin 11.2311.6411.9710.6111.28 Skin penetration enhancer Isopropyl myristate-----Sorbitan monooleate-----Solubilizer N-Methyl-2-pyrrolidone 4.454.234.354.214.47 Caprylaulate 4.454.234.354.214.47 Total 100.00100.00100.00100.00100.00

[0086] Experimental Example 1. Transdermal Permeation Test

[0087] A Franz diffusion cell was used for the transdermal permeation test. The aqueous phase was maintained at 32°C in a pH 7.4 phosphate buffer containing 0.5% sodium azide, and stirred at 600 rpm throughout the experiment.

[0088] The transdermal absorbents manufactured in the examples and comparative examples above were cut into 0.738 cm2 circles and attached onto human cadaver skin epidermis. Then, they were mounted on a diffusion device for drug permeation experiments, and 100 μL was taken and analyzed by HPLC.

[0089] For the transdermal absorption preparations of the above examples and comparative examples, the cumulative permeation amount (㎍ / ㎠) of the effective drug after 12 hours, the cumulative permeation amount (%) compared to the initial content of the effective drug, and the skin permeation rate (㎍ / ㎠ / h) of the effective drug were analyzed, and the results are shown in Tables 4 to 8 below, respectively.

[0090] KetoprofenEffective drug cumulative permeation amount (㎍ / ㎠)Effective drug Cumulative permeation amount compared to initial content (%)Effective drug Skin permeation rate (㎍ / ㎠ / h)Example 1155.06±24.936.186.46Comparative example 174.31±7.817.343.10Comparative example 286.10±8.520.093.59Comparative example 3123.04±10.828.715.13Comparative example 653.49±10.412.482.23Comparative example 7103.29±12.924.104.30Comparative example 8119.36±9.727.854.97Comparative example 9129.60±17.3.130.245.40Comparative example 10116.53±10.827.194.86Comparative example 12162.86±12.138.006.79

[0091] Diclofenac sodium Effective drug cumulative permeation amount (㎍ / ㎠) Effective drug Cumulative permeation amount compared to initial content (%) Effective drug skin permeation rate (㎍ / ㎠ / h) Example 2 143.66 ± 21.0 3 3.5 2 5.99 Comparative example 4 137.49 ± 7.1 3 2.0 8 5.73

[0092] Tramadol Effective drug cumulative permeation amount (㎍ / ㎠) Effective drug cumulative permeation amount compared to initial content (%) Effective drug skin permeation rate (㎍ / ㎠ / h) Example 3 127.33±13.8 29.7 15.31 Comparative example 5 121.76±11.3 28.4 15.07

[0093] Lidocaine Effective drug cumulative permeation amount (㎍ / ㎠) Effective drug Cumulative permeation amount compared to initial content (%) Effective drug skin permeation rate (㎍ / ㎠ / h) Example 183.67±8.8 32.54 3.49 Example 278.45±7.3 30.5 13.27 Example 387.38±5.0 33.98 3.64 Comparative example 163.82±3.5 24.8 22.66 Comparative example 256.47±7.9 21.96 2.35

[0094] AmitriptylineEffective drugCumulative permeation amount (㎍ / ㎠)Effective drugCumulative permeation amount compared to initial content (%)Effective drugSkin permeation rate (㎍ / ㎠ / h)Example 182.18±8.831.963.42Example 278.53±7.330.543.27Example 387.97±5.034.213.67Comparative example 167.65±3.526.312.82Comparative example 265.96±7.925.652.75Comparative example 1182.16±6.131.953.42

[0095] As a result, as can be seen from the results in Tables 4 to 8 above, the transdermal absorption preparations of Examples 1 to 3 using SIS as an adhesive agent showed significantly higher effects in terms of cumulative permeation amount of effective drug, cumulative permeation amount compared to initial content, and skin permeation rate than the transdermal absorption preparations of Comparative Example 1 using Durotak 2052, an acrylic polymer, Comparative Example 2 using polyisobutylene, a synthetic rubber polymer, Comparative Example 6 using NR, Comparative Example 7 using SBS, or Comparative Example 8 using SEP.

[0096] In addition, as can be seen from the results in Tables 4, 7 and 8 above, the transdermal absorption preparations of Examples 1 to 3 including not only an adhesive agent but also an adhesive-imparting resin and a plasticizer showed an effect in which the content of the drug released from the transdermal absorption preparation was about 1.2 to 2 times higher than that of the transdermal absorption preparation of Comparative Example 1 not including an adhesive-imparting resin and a plasticizer.

[0097] In particular, as can be seen from the results in Table 4 above, the transdermal absorption preparation of Example 1 using terpene resin and rosin ester resin as the adhesive resin showed significantly higher effects in terms of cumulative permeation amount of the effective drug, cumulative permeation amount compared to the initial content, and skin permeation rate than the transdermal absorption preparation of Comparative Example 9 using an aliphatic hydrocarbon resin or Comparative Example 10 using an alicyclic hydrocarbon resin.

[0098] Furthermore, as can be seen from the results in Table 8 above, the transdermal absorption preparations of Examples 1 to 3 that did not use a skin penetration enhancer showed similar or higher effects than the transdermal absorption preparation of Comparative Example 11 that used a skin penetration enhancer in terms of cumulative permeation amount of the effective drug, cumulative permeation amount compared to the initial content, and skin permeation rate.

[0099] In addition, as can be seen from the results in Tables 4 to 6 above, the transdermal absorption preparations of Examples 1 to 3, which were manufactured in a ratio of 1.1:2.2:4.4:1.2 of effective drug: adhesive base: adhesive resin: plasticizer, showed significantly higher effects in terms of cumulative permeation amount of effective drug, cumulative permeation amount compared to initial content, and skin permeation rate than the transdermal absorption preparations of Comparative Examples 3 to 5, which were manufactured in a ratio of 1.1:2.2:3.4:1.2.

[0100] This suggests that the drug delivery effect of the transdermal absorption preparation is enhanced when the transdermal absorption preparation includes a drug, an adhesive, an adhesive-imparting resin, and a plasticizer, and when SIS is used as the adhesive, and terpene resin and rosin ester resin are used as the adhesive. In addition, it suggests that the transdermal absorption preparation must be manufactured in the ratio and composition according to Examples 1 to 3 to effectively deliver the effective drug, and in particular, that the effective drug delivery is effectively achieved even without using a skin penetration enhancer.

[0101] In addition, for the transdermal absorption preparations of Example 4 and Comparative Examples 13 to 17, the cumulative permeation amount (㎍ / ㎠) of the effective drug after 24 hours, the cumulative permeation amount (%) compared to the initial content of the effective drug, and the skin permeation rate (㎍ / ㎠ / h) of the effective drug were analyzed, and the results are shown in Table 9 below.

[0102] KetoprofenEffective drug cumulative permeation amount (㎍ / ㎠)Effective drug Cumulative permeation amount compared to initial content (%)Effective drug Skin permeation rate (㎍ / ㎠ / h)Example 4 137.14±11.2 32.00 5.71Comparative example 13 130.58±15.1 30.47 5.44Comparative example 14 134.50±18.4 31.38 5.60Comparative example 15 122.32±10.7 28.5 4 5.10Comparative example 16 125.49±13.4 29.28 5.23Comparative example 17 123.27±10.3 28.76 5.14

[0103] Experimental Example 2. Skin Irritation Test

[0104] The transdermal absorption preparations manufactured in the examples and comparative examples above were attached to the dorsum of the experimental rabbits after hair removal, and erythema, crust formation, and edema formation were observed and evaluated after 12 and 24 hours.

[0105] As shown in Table 10 below, skin reaction scores were evaluated by time zone according to the "Draize's Skin Reaction Evaluation Table (Draize's Criteria: 1959)", and the average score was calculated by dividing the sum of the skin reaction scores by the number of subjects. As shown in Table 11 below, the primary skin irritation index (PII) was calculated by dividing the sum of the average scores by 4 to evaluate the degree of skin irritation. The results of the evaluation and analysis are shown in Table 12 below.

[0106] * Average score = Sum of skin reaction scores by time zone / Number of individuals

[0107] * PII = Sum of average scores / 4

[0108] Draize's Skin Reaction Evaluation Table (Draize's criteria: 1959) Reaction score Erythema and crusting - No erythema at all 0 - Very mild erythema (barely discernible to the naked eye) 1 - Marked erythema 2 - Slightly severe erythema 3 - Severe erythema (beet-colored redness) and mild crusting 4 Highest score = 4 Edema - No edema 0 - Very mild edema (barely discernible to the naked eye) 1 - Mild edema (distinctly swollen with a clearly distinguishable margin) 2 - Moderate edema (swelling of about 1 mm) 3 - Severe edema (swelling of more than 1 mm and extending beyond the exposed area) 4 Highest score = 4

[0109] Primary Skin Irritation Index (PII) Primary Skin Irritation Index (PII) Classification 0 Non-irritating 0 < PII ≤ 2 Mild irritating 2 < PII ≤ 5 Moderate irritating 8 < PII ≤ 8 Strong irritating

[0110] Formulation name Primary skin irritation index Example 10.00 Example 20.00 Example 30.00 Comparative example 10.27 Comparative example 30.18 Comparative example 40.24

[0111] As a result, as shown above, it was confirmed that the transdermal absorption preparation according to the present invention does not cause significant skin irritation.

[0112] Experimental Example 3. Residual drug amount after skin application

[0113] The transdermal preparations manufactured in the previous examples and comparative examples were cut and applied to human shoulder skin. After 24 hours, the transdermal preparations were removed from the skin, and the amount of drug released from the transdermal preparations was calculated by measuring the content of residual drug within the transdermal preparations. The results are presented in Tables 13 to 17 and Figures 2 to 8.

[0114] Ketoprofen Total drug content in transdermal preparation (mg / 70㎠) Residual drug in transdermal preparation (mg / 70㎠) Drug released from transdermal preparation (mg / 70㎠) Example 1 30.00 18.60±0.82 11.40±0.75 Example 4 30.00 17.97±0.52 12.03±0.29 Example 5 30.00 19.87±0.84 10.13±0.24 Comparative Example 1 30.00 24.45±0.6 35.55±0.91 Comparative Example 2 30.00 23.94±0.47 6.06±0.45 Comparative Example 3 30.00 26.73±0.4 13.27±0.66 Comparative Example 630.0025.77±0.614.23±0.25Comparative example 730.0021.57±0.198.43±0.81Comparative example 830.0019.88±0.3710.12±0.45Comparative example 930.0021.14±0.218.86±0.90Comparative example 1030.0020.48±0.179.52±0.48Comparative example 1230.0017.04±0.4112.96±0.29

[0115] Total drug content in diclofenac sodium transdermal preparation (mg / 70㎠) Residual drug in transdermal preparation (mg / 70㎠) Drug released from transdermal preparation (mg / 70㎠) Example 2 30.00 19.26±0.7 2 7.0±0.61 Comparative example 4 30.00 24.23±0.4 4 5.6±0.78

[0116] Total drug content in tramadol transdermal preparation (mg / 70㎠) Residual drug in transdermal preparation (mg / 70㎠) Drug released from transdermal preparation (mg / 70㎠) Example 3 30.00 2 1.74±0.5 8 8.27±0.69 Comparative example 5 30.00 2 4.36±0.6 1 5.64±0.14

[0117] Lidocaine Total drug content in transdermal preparation (mg / 70㎠) Residual drug in transdermal preparation (mg / 70㎠) Drug released from transdermal preparation (mg / 70㎠) Example 1 18.00 1 1.77±0.8 0 6.23±0.17 Example 2 18.00 1 1.01±0.7 3 6.99±0.31 Example 3 18.00 1 2.21±0.6 1 5.79±0.19 Comparative example 1 18.00 1 4.14±0.3 5 3.86±0.36 Comparative example 2 18.00 1 3.61±0.2 1 4.39±0.53

[0118] Amitriptyline Total drug content in transdermal preparation (mg / 70㎠) Residual drug in transdermal preparation (mg / 70㎠) Drug released from transdermal preparation (mg / 70㎠) Example 1 18.00 1 2.28±0.38 5.72±0.47 Example 2 18.00 1 2.02±0.27 5.98±0.14 Example 3 18.00 1 1.79±0.60 6.21±0.39 Comparative example 1 18.00 1 4.21±0.14 3.79±0.26 Comparative example 2 18.00 1 5.86±0.41 2.14±0.56 Comparative example 1 18.00 1 4.63±0.24 3.37±0.41

[0119] As a result, as can be seen from the results in Tables 13 to 17 and FIGS. 2, 3, 7 and 8, the transdermal absorption preparations of Examples 1 to 5 using SIS as an adhesive agent showed significantly higher effects on the drug content released from the transdermal absorption preparations than the transdermal absorption preparations of Comparative Example 1 using Durotak 2052, an acrylic polymer, Comparative Example 2 using polyisobutylene, a synthetic rubber polymer, Comparative Example 6 using NR, Comparative Example 7 using SBS or Comparative Example 8 using SEP.

[0120] In addition, as can be seen from the results in Tables 13, 16 and 17 and FIGS. 2, 3, 7 and 8, the transdermal absorption preparations of Examples 1 to 5 including not only an adhesive agent but also an adhesive-imparting resin and a plasticizer showed an effect that was about 1.5 to 2 times higher in terms of the content of drug released from the transdermal absorption preparation than the transdermal absorption preparation of Comparative Example 1 that did not include an adhesive-imparting resin and a plasticizer.

[0121] In particular, as can be seen from the results in Table 13 and FIG. 4, the transdermal absorption preparation of Example 1 using terpene resin and rosin ester resin as the adhesive resin showed a significantly higher effect on the released drug content than the transdermal absorption preparation of Comparative Example 9 using an aliphatic hydrocarbon resin or Comparative Example 10 using an alicyclic hydrocarbon resin.

[0122] Furthermore, as can be seen from the results in Table 17 and FIG. 8, the transdermal absorption preparations of Examples 1 to 5 that did not use a skin penetration enhancer showed a higher effect on the drug content released from the transdermal absorption preparation than the transdermal absorption preparation of Comparative Example 11 that used a skin penetration enhancer.

[0123] In addition, as can be seen from the results in Tables 13 to 17 and FIGS. 2, 3, 5 and 6, the transdermal absorption preparations of Examples 1 to 5, which were prepared in a ratio of effective drug: adhesive base: adhesive resin: plasticizer of 1 to 1.5: 1.5 to 3: 4 to 5: 0.5 to 2, exhibited significantly higher effects on the released drug content than the transdermal absorption preparations of Comparative Examples 3 to 5, which were prepared in a ratio of 1.1: 2.2: 3.4: 1.2.

[0124] In particular, as can be seen in the results in Table 13 and FIG. 2, in the case of the transdermal absorption preparation of Comparative Example 3, not only was the content of the effective drug (ketoprofen) more than twice that of the transdermal absorption preparation of Example 1 higher, but it also contained a skin penetration enhancer, but the released content was reduced by about 80% compared to Example 1. This suggests that the drug administration effect of the transdermal absorption preparation is higher when the transdermal absorption preparation contains an adhesive agent, a tackifying resin, and a plasticizer together with the drug, and when SIS is used as the adhesive agent, and terpene resin and rosin ester resin are used as the tackifying resin. In addition, it suggests that the transdermal absorption preparation must be manufactured in the ratio and composition according to Examples 1 to 5 to effectively deliver the effective drug, and in particular, that the delivery of the effective drug is effectively delivered even without using a skin penetration enhancer.

[0125] Additionally, the transdermal absorption preparations of Example 4 and Comparative Examples 13 to 17 were cut and attached to the skin of the human shoulder area. After 24 hours, the transdermal absorption preparations were removed from the skin, and the amount of drug released from the transdermal absorption preparations was calculated by measuring the content of residual drug within the transdermal absorption preparations. The results are shown in the table below.

[0126] KetoprofenTotal drug content in transdermal preparation (mg / 70㎠)Residual drug in transdermal preparation (mg / 70㎠)Drug released from transdermal preparation (mg / 70㎠)Example 430.0017.40±0.5212.60±0.29Comparative example 1330.0018.00±2.1512.00±0.54Comparative example 1430.0017.64±0.7212.36±0.77Comparative example 1530.0018.76±0.5611.24±0.32Comparative example 1630.0018.47±0.3711.53±0.56Comparative example 1730.0018.68±0.5911.33±0.30

[0127] As a result, as can be seen from the results in the table above, the transdermal absorption preparations of Comparative Example 13, which was manufactured in a ratio of active drug: adhesive base: adhesive-imparting resin: plasticizer = 1.1:1.65:4.13:1.01, and Comparative Examples 14 to 17, in which the amounts of adhesive base, adhesive-imparting resin, and plasticizer were adjusted, exhibited a lower transdermal absorption rate than the transdermal absorption preparation of Example 4 in terms of cumulative permeation amount of active drug, cumulative permeation amount compared to the initial content, and skin permeation, and problems such as decreased adhesive strength and crystal precipitation were discovered as a result of a 4-week stability test.

[0128] This is thought to be the result of the drug quickly moving to the surface and being redistributed due to the lower affinity between the active drug and the adhesive in the transdermal absorption preparations of Comparative Examples 13 to 17 compared to Example 4, and it also seems to be the result of the lower adhesion to the adherend due to the lower adhesive force caused by reasons such as crystal formation.

[0129] Experimental Example 4. Long-term storage test

[0130] The long-term storage potential of the transdermal absorption preparations manufactured in the above examples and comparative examples was analyzed. This was confirmed by observing whether crystals were formed in the transdermal absorption preparations.

[0131] Specifically, each percutaneous absorption agent was molded into 10㎠, placed in a petri dish, and stored under accelerated test conditions of 40℃ and 75% relative humidity. Thereafter, after 1 week, 2 weeks, and 4 weeks, the crystal formation results were visually observed, and the degree of crystal precipitation was organized into a diagram of X (no crystal formation), Δ (suspected crystal formation), or O (crystal formation), and is shown in the table below.

[0132] Storage periodExample 1Example 2Example 3Comparative example 3Comparative example 4Comparative example 5Comparative example 121 weeksXXXΔOΔΔ2 weeksXXXOOOO4 weeksXXXOOOO

[0133] Storage period Example 4 Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 1 week X△XX△△2 weeks XOX△△O 4 weeks XOXOOO

[0134] As a result, as can be seen from the results in the table above, in the transdermal absorption preparations of Examples 1 to 3, in which SIS was used as the adhesive agent, terpene resin and rosin ester resin were used as the adhesive-imparting resin, and the effective drug: adhesive agent: adhesive resin: plasticizer were manufactured in a ratio of 1 to 1.5: 1.5 to 3: 4 to 5: 0.5 to 2, no crystals were formed even when stored for a long period of 4 weeks or more.

[0135] However, in the transdermal absorption preparations of Comparative Examples 3 to 5, which were manufactured in a ratio of 1.1:2.2:3.4:1.2 of effective drug: adhesive base: adhesive resin: plasticizer, although SIS was used as the adhesive agent and terpene resin and rosin ester resin were used as the adhesive resin, crystals began to form even during a short storage period of 1 week, and after 2 weeks, a large amount of crystals were formed that could not be attached to the skin, and the physical properties also deteriorated.

[0136] In addition, although SIS was used as an adhesive agent, and terpene resin and rosin ester resin were used as adhesive-imparting resins, in the transdermal absorption preparation of Comparative Example 12, which was manufactured in a ratio of effective drug: adhesive agent: adhesive resin: plasticizer of 1.7:2.2:3.8:1.2, crystals began to form even during a short storage period of 1 week, and after 2 weeks, a large amount of crystals were formed that could not be attached to the skin, and the physical properties also deteriorated.

[0137] In addition, although SIS was used as an adhesive agent, and terpene resin and rosin ester resin were used as adhesive-imparting resin, the drug: adhesive agent: adhesive resin: plasticizer ratio was 1.1:1.65:4.13:1.01, in Comparative Example 13 and Comparative Examples 15 to 17 in which the usage ratio of each component in Comparative Example 13 was adjusted, most of the transdermal absorption preparations began to form crystals even during a short storage period of 1 week, and after 2 weeks, a large amount of crystals were formed that could not be attached to the skin, and the physical properties also deteriorated. The fact that crystals were not formed in Comparative Example 14 is thought to be due to the decrease in the cohesiveness of the preparation, which increased the compatibility between the drug and the preparation.

[0138] This suggests that when a transdermal absorption preparation is manufactured with the ratio and composition according to Examples 1 to 5, the problem of the drug precipitating into crystals or the resulting deterioration of physical properties does not occur even during long-term storage, the effective drug can be maintained at a saturated concentration, and all components in the preparation are uniformly dispersed without agglomeration, so that the effective drug is effectively delivered.

[0139] Experimental Example 5. Adhesion Test

[0140] The adhesive strength of the transdermal absorption preparations manufactured in the above examples and comparative examples was analyzed.

[0141] Specifically, each transdermal absorption agent was placed in a petri dish, stored under accelerated test conditions of 40℃ and 75% relative humidity, and tested according to the adhesive strength test method in the adhesive bandage section of the Korean Pharmacopoeia, and the results are shown in the table below.

[0142] Adhesion (g / 12mm) Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 121 weeks 211.00 187.28 170.20 187.79 164.23 152.11 150.21 4 weeks 220.49 167.89 168.74 146.38 120.5 1110.93 125.73

[0143] Adhesion (g / 12mm) Example 4 Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 1 week 197.71 158.14 2 11.56 163.57 175.21 165.87 4 week 185.47 128.70 2 32.49 149.54 140.93 149.62

[0144] As a result, as can be seen from the results in the table above, the transdermal absorption preparations of Examples 1 to 3, which used SIS as the adhesive agent, terpene resin and rosin ester resin as the adhesive-imparting resin, and were manufactured in a ratio of effective drug: adhesive agent: adhesive resin: plasticizer of 1 to 1.5: 1.5 to 3: 4 to 5: 0.5 to 2, exhibited high adhesive strength, and the adhesive strength was maintained at a similar level to the initial level even after a long period of 4 weeks or more.

[0145] However, in the transdermal absorption preparations of Comparative Examples 3 to 5, which were prepared in a ratio of 1.1:2.2:3.4:1.2 of effective drug: adhesive base: adhesive resin: plasticizer, even though SIS was used as the adhesive agent and terpene resin and rosin ester resin were used as the adhesive resin, the adhesive strength began to decrease even during a short storage period of 1 week, and after 4 weeks, the adhesive strength decreased to the extent that it could not be attached to the skin, and the physical properties also deteriorated.

[0146] In addition, SIS was used as an adhesive agent, and terpene resin and rosin ester resin were used as adhesive-imparting resins. However, in the transdermal absorption preparation of Comparative Example 12, which was manufactured in a ratio of 1.7:2.2:3.8:1.2 of effective drug: adhesive agent: adhesive resin: plasticizer, the adhesive strength was significantly reduced even in a short period of 1 week, and after 4 weeks, the adhesive strength was reduced by about 20% or more compared to the 1st week.

[0147] In addition, SIS was used as an adhesive agent, and terpene resin and rosin ester resin were used as adhesive-imparting resin, but in Comparative Example 13, which was manufactured in a ratio of drug: adhesive agent: adhesive resin: plasticizer of 1.1:1.65:4.13:1.01, and in Comparative Examples 15 to 17, which adjusted the usage ratio of each component in Comparative Example 13, the adhesive strength was reduced due to changes in physical properties such as crystal formation, and the change was further reduced during the stability test period.

[0148] In addition, although SIS was used as an adhesive agent, and terpene resin and rosin ester resin were used as adhesive-imparting resins, the high adhesive strength of the transdermal absorption preparation of Comparative Example 14, manufactured in a ratio of drug: adhesive agent: adhesive resin: plasticizer of 1.1:1.65:4.13:1.01, is thought to be due to the low cohesiveness of the preparation to the extent that it was difficult to use as a product, resulting in the drug being transferred to the adherend.

[0149] This suggests that when a transdermal absorption preparation is manufactured with the ratio and composition according to Examples 1 to 5, the problem of the drug precipitating into crystals or the resulting deterioration of physical properties does not occur even during long-term storage, the effective drug can be maintained at a saturated concentration, all components in the preparation can be uniformly dispersed without agglomeration, and the adhesive force to the skin is maintained similar to that at the time of manufacture, so that the effective drug is effectively delivered.

Claims

1. In a percutaneous absorption preparation comprising a) a support layer and b) a matrix layer, A transdermal absorption preparation, wherein the matrix layer comprises (i) an active drug, (ii) an adhesive agent, (iii) an adhesive-imparting resin, and (iv) a plasticizer.

2. In paragraph 1, A transdermal absorption preparation wherein the above effective drug is at least one selected from the group consisting of non-steroidal anti-inflammatory drugs, analgesics, local anesthetics, and antidepressants.

3. In paragraph 2, A transdermal absorption preparation wherein the non-steroidal anti-inflammatory agent is at least one selected from the group consisting of ketoprofen, flurbiprofen, loxoprofen, diclofenac, felbinac, indomethacin, piroxicam, ketorolac, mefenamic acid, and salicylic acid.

4. In paragraph 2, A transdermal absorption agent, wherein the above analgesic is at least one selected from the group consisting of acetaminophen, ibuprofen, tramadol, and buprenorphine.

5. In paragraph 2, A transdermal absorption preparation wherein the local anesthetic is at least one selected from the group consisting of procaine, chloroprocaine, tetracaine, prilocaine, lidocaine, mepivacaine, bupivacaine, ropivacaine, and etidocaine.

6. In paragraph 2, A transdermal absorption agent, wherein the antidepressant is at least one selected from the group consisting of norepinephrine-reuptake inhibitors (NRls), selective serotonin-reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin and noradrenaline-reuptake inhibitors ("SNRls"), corticotropin-releasing factor (CRF) antagonists, alpha-adrenoceptor antagonists, NKl-receptor antagonists, 5-HT1A-receptor agonists, 5-HT1A-receptor antagonists, 5-HT1A-receptor partial agonists and atypical antidepressants.

7. In paragraph 2, The above antidepressant is a tricyclic antidepressant, a transdermal absorption agent.

8. In paragraph 1, A transdermal absorption preparation wherein the above matrix layer does not contain a skin penetration enhancer.

9. In paragraph 8, A transdermal absorption preparation wherein the above skin penetration enhancer is isopropyl myristate or sorbitan monooleate.

10. In paragraph 1, A transdermal absorption preparation wherein the adhesive agent is a styrene-isoprene-styrene block copolymer (SIS).

11. In paragraph 1, A transdermal absorption preparation wherein the adhesive resin is a natural resin, a synthetic resin or a mixture thereof.

12. In paragraph 1, A transdermal absorption preparation, wherein the adhesive-imparting resin is at least one selected from the group consisting of rosin-based resin and terpene-based resin.

13. In paragraph 1, A transdermal absorption preparation, wherein the plasticizer is at least one selected from the group consisting of petroleum oil, squalane, squalene, vegetable oil, synthetic oil, dibasic acid ester, liquid rubber, liquid isoprene rubber, liquid fatty acid ester, diethylene glycol, polyethylene glycol, salicylic acid glycol, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, clotamiton, caprylpyrrolidone, and laurylpyrrolidone.

14. In paragraph 1, A transdermal absorption preparation, wherein the weight ratio of the above (i) effective drug, (ii) adhesive agent, (iii) adhesive-imparting resin, and (iv) plasticizer is 1 to 1.5 : 1.5 to 3 : 4 to 5 : 0.5 to 2.

15. In paragraph 1, A transdermal absorption preparation, wherein the above effective drug is contained in an amount of 0.5 mg / cm2 or more and less than 2 mg / cm2 per unit area of ​​the matrix layer.

16. In paragraph 1, A transdermal absorption preparation that does not include an intermediate film or adhesive layer.

17. In paragraph 1, The above transdermal absorption preparation further comprises c) a peeling layer.

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