WO2013020527A1 - Utilisation d'alaptide en tant que modificateur de pénétration transdermique dans des compositions pharmaceutiques pour des applications humaines et vétérinaires contenant des médicaments anti-inflammatoires et/ou des agents chimiothérapeutiques antimicrobiens - Google Patents

Utilisation d'alaptide en tant que modificateur de pénétration transdermique dans des compositions pharmaceutiques pour des applications humaines et vétérinaires contenant des médicaments anti-inflammatoires et/ou des agents chimiothérapeutiques antimicrobiens Download PDF

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WO2013020527A1
WO2013020527A1 PCT/CZ2012/000073 CZ2012000073W WO2013020527A1 WO 2013020527 A1 WO2013020527 A1 WO 2013020527A1 CZ 2012000073 W CZ2012000073 W CZ 2012000073W WO 2013020527 A1 WO2013020527 A1 WO 2013020527A1
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alaptide
penetration
acid
addition
ala
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PCT/CZ2012/000073
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English (en)
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Josef JAMPÍLEK
Radka OPATŘILOVÁ
Lenka COUFALOVÁ
Aneta ČERNÍKOVÁ
Jiří DOHNAL
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University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy
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Priority claimed from CZ2011-495A external-priority patent/CZ304915B6/cs
Priority claimed from CZ2012-72A external-priority patent/CZ306770B6/cs
Priority claimed from CZ2012-511A external-priority patent/CZ306686B6/cs
Application filed by University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy filed Critical University Of Veterinary And Pharmaceutical Sciences Brno Faculty Of Pharmacy
Publication of WO2013020527A1 publication Critical patent/WO2013020527A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • Alaptide as Transdermal Penetration Modifier in Pharmaceutical Compositions for Human and Veterinary Applications Containing Anti-inflammatory Drugs and/or Antimicrobial Chemotherapeutics.
  • the invention deals with utilization of (3 ⁇ 4-8-methyl-6,9-diazaspiro[4.5]decan-7, 10-dione, known by the international non- roprietary name of "alaptide”, as a pharmaceutical adjuvant (excipient) for modification of transdermal penetration of drugs in pharmaceutical formulations convenient for transdermal application, i.e.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/ antimycobacterials, antimycotics, antivirotics.
  • Transdermal therapeutic systems represent an excellent alternative to conventional pharmaceutical dosage forms.
  • the application of transdermal drug delivery faces the problem of insufficient or no penetration of active pharmaceutical substances through the skin.
  • some physical or chemical possibilities/approaches for overcoming the skin barrier were developed.
  • the idea of percutaneous drug absorption appeared long ago; the Ebers papyrus mentioned it as early as the 16 th century B.C. In 1975 Idson stated that the epidermic barrier was a limiting factor for percutaneous absorption and that once the drug passed through stratum cvrneum (SC) of the epidermis, its absorption was guaranteed.
  • SC stratum cvrneum
  • Transdermal therapeutic systems or transdermal drug delivery systems are topical dosage forms intended to deliver a drug substance at a controlled rate through the intact skin into the systemic circulation and to maintain efficacious plasma levels during prolonged time.
  • a characteristic feature of TTSs in comparison with other topical dosage forms is the transport of defined and precise drug dosages through the healthy skin per defined time. The area-dosage-time relationships are determined as a crucial factor.
  • Predecessors of TTSs were semi-solid topical dosage forms, mostly ointments, with the expected systemic effect. For some indications TTSs have already been used in clinical practice for the treatment of a variety of systemic diseases, for certain drugs they are tested or clinical trials are performed nowadays.
  • At present transdermally applicable drugs include glycerol trinitrate, scopolamine, nicotine, oxybutynin, contraceptives, anodynes (e.g., fentanyl, buprenorphine), antihypertensive or antiarythmic drugs (e.g., clonidine, propranolol), drugs against pain/inflammatory or antiparkinsonics (rotigotine).
  • anodynes e.g., fentanyl, buprenorphine
  • antihypertensive or antiarythmic drugs e.g., clonidine, propranolol
  • drugs against pain/inflammatory or antiparkinsonics rotigotine.
  • a number of new pharmaceuticals are developed or even under clinical evaluation, for example antipsychotics, non-steroidal hormones or antineoplastics (e.g., physostigmine, selegiline, insulin or 5-fluorouracil).
  • transdermal administration includes, above all, good pharmacokinetic properties of application systems, the ability to maintain long-lasted stationary plasma levels of active substances, including drugs with short biological half-lives, which reduces undesirable side effects occurring as a result of considerable fluctuations of drug plasma levels.
  • the plasma levels achieved with the use of conventional dosage forms exhibit peaks and may even reach a toxic level leading to complications.
  • Presystemic elimination of the applied dosage hepatic first-pass effect
  • such effects as pH change in the GIT or interactions with simultaneously applied preparations or food are also prevented effectively.
  • TTSs also provide a possibility to apply drugs with a narrow therapeutic window and to interrupt drug delivery to the system immediately in the case of undesirable effect occurrence (in contrast to other conventional dosage forms, which do not provide such a possibility).
  • TTSs are a noninvasive alternative to parenteral, subcutaneous and intramuscular injections ⁇ Jampilek, J. et al. Med. Res. Rev., in press, DOI 10.1002/med.20227; Delgado-Charro, M.B. & Guy, R.H. Transdermal drug delivery, In: Drug Delivery and Targeting, Hillery A.M., Lloyd A. W., Swarbrick J. (Eds.), Taylor & Francis, London, pp.207-236; Rabiskova M. et al. Technology of Pharmaceutics, 3rd ed., Galen Prague, 2006).
  • the skin is a human organ with the largest area and consists of three basic functional layers: the upper layer (epidermis), corium (dermis), and subcutaneous tissue (hypodermis). These layers localize capillaries, nerve endings and skin appendages (hair, nails and sebaceous, sweat and apocrine glands).
  • the skin performs a number of different functions; the most important is protection from excessive water loss and mechanical, chemical, microbial and physical impacts. The most important is the outermost layer of epidermis, the horny layer (stratum corneum, SC), which is in fact the skin barrier.
  • the structure of the SC can be described as a "bricks and mortar” model: corneocytes rich in keratin represent hydrophilic "bricks", and the lipid matrix represents hydrophobic "mortar” (Forslind, B. & Lindberg, M. Skin, Hair, Nails: Structure and Function. Marcel & Dekker New York, 2004; McGrath, J. A. et al. Rook's Textbook of Dermatology, 7th ed., Blackwell Publishing, 2004; Jampilek, J. et al. Med. Res. Rev., in press, DOI 10.1002/med.20227). ⁇
  • the penetration through the least permeable layer, the SC is a limiting process.
  • the live epidermis acts as a barrier only for penetration of extremely lipophilic compounds.
  • the last two routes of drug penetration to the organism are considered as the most probable; together they are sometimes denominated as transepidermal (Karande, P. et al. Proc. Natl. Acad. Sci.
  • the skin barrier for facilitation of drug penetration can be affected by physical skin penetration enhancement techniques, including iontophoresis, electroporation acoustical methods and microneedles.
  • physical skin penetration enhancement techniques including iontophoresis, electroporation acoustical methods and microneedles.
  • the disadvantage of these methods is their comparatively complicated use requiring special apparatus for their application and consequent financial cost; therefore mostly chemical transdermal penetration enhancers are used.
  • CPEs transdermal chemical penetration enhancers
  • These compounds are able to specifically affect intercellular space between corneocytes or modify corneocytes by hydration or denaturation of keratin, see details below (Karande, P. et al. Proc. Natl. Acad. Sci.
  • An ideal enhancer should: i) be nontoxic, non-irritating and cause no allergic reactions; ii) have reversible influence on the skin barrier; after removal the skin should immediately and fully recover its normal barrier functions; Hi) possess rapid onset of action with a predictable and repeatable effect; iv) be pharmacologically and chemically inert; v) act selectively in one direction, i.e.
  • CPEs From the chemical point of view the group of CPEs is very heterogeneous. All CPEs were divided into 10 categories that covered the broad spectrum of evaluated compounds: i) anionic surfactants, ii) cationic surfactants, Hi) zwitterionic surfactants, iv) non-ionic surfactants, v) fatty acids, vi) sodium salts of fatty acids, vii) fatty esters, viii) fatty amines, ix) Azone-like compounds, and x) others (e.g., calcium thioglycolate, menthol, urea, cyclodextrins).
  • anionic surfactants ii) cationic surfactants, Hi) zwitterionic surfactants, iv) non-ionic surfactants, v) fatty acids, vi) sodium salts of fatty acids, vii) fatty esters, viii) fatty amines, ix) Azone-like compounds, and x) others
  • CPEs can interact with the intercellular lipid matrix (especially ceramides), or ii) they can interact with protein structures (influencing the conformation of keratin in the corneocytes or proteins in desmosomes), or Hi) CPEs can promote partitioning (influencing the SC nature leads to raising the penetrant concentration gradient and thus increasing the flux, i.e. increasing the concentration of the drug in the skin).
  • Alaptide (S)-8-methyl-6,9-diazaspiro[4.5]decan-7,10-dione (see Fig. 1), is a compound discovered in the 1980s at Prague by Kasafirek et al. The substance preparation, production procedures and therapeutic application were protected by a number of patents in Czechoslovakia/the Czech Republic and abroad. Alaptide showed significant curative effect in different therapeutic areas on experimental animal models and also demonstrated very low acute toxicity in rats and mice. Furthermore, teratogenic and embryotoxic effects of alaptide were not observed. Evaluation of subchronic and chronic toxicity was carried out in rats in the dosage of 20 mg/ml and dogs in the dosage of 10 mg/ml, and no toxic effects were registered.
  • alaptide enantiomers were tested in metabolic and induction studies on primary human hepatocyte cultures. It was found that the alaptide enantiomers do not induce biotransformation enzymes CYPIAI, CYP1A2 and CYP1B1 in hepatocytes. These biotransformation enzymes are critical in bioactivation of procarcinogens (such as polychlorinated aromatic hydrocarbons or planar hydrocarbons) and are upregulated also by ultraviolet-B radiation (UVB) in the skin.
  • procarcinogens such as polychlorinated aromatic hydrocarbons or planar hydrocarbons
  • CYPIAI is involved in the metabolic activation of aromatic hydrocarbons from pollution or industry contamination (polycyclic aromatic hydrocarbons such as benzopyrene, BP) by transforming it to BP-7,8-dihydrodiol-9,10- epoxide, which is the ultimate carcinogen.
  • UVB-mediated induction of cytochromes CYP1A1 and CYP1B1 in human skin will probably result in enhanced bioactivation of polycyclic aromatic hydrocarbons and other environmental pollutants to which humans are exposed, which in turn could make the human skin more susceptible to UVB -induced skin cancers or allergic and irritant contact dermatitis ⁇ Jampilek, J. et al.
  • non-steroidal anti-inflammatory drugs otherwise nonsteroidal antiphlogistics or NSADDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/antimycobacterials, antimycotics, antivirotics
  • non-steroidal anti-inflammatory drugs are sampled from the following list: phenylbutazone, oxyphenbutazone, kebuzone, tribuzone, sulfinpyrazone, azapropazone, mofebutazone, clofezon, suxibuzone, flufenamic acid, niflumic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, aclantate, etofenamate, flunixine, ibufenac, alclofenac, diclofenac, indometacin, acemetacin, tropesin, sulindac, lonazolac, tolmetin, ketorolac, nabumetone, fenbumetone, indobufene, zomepirac, bumadizone, etodolac, fenti
  • the used antipyretics/non-opiate analgesics are sampled from the following list: paracetamol, bucetin, propacetamol, salicylic acid, acetylsalicylic acid, choline salicylate, lysine salicylate, salicylate sodium or potassium, imidazole salicylate, morpholine salicylate, salsalate, ethenzamide, guacetisal, carbasalate calcium, salicylamide, methylsalicylate, aloxiprin, lysine acetylsalicylate, benorilate, gentisie acid, dipyrocetyl, diflunisal, phenazone, aminophenazone, propyphenazone, ramiphenazone, metamizole, rimazoline, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide, menthol, nabiximols
  • the used glucocorticoids are sampled from the following list: hydrocortisone, hydrocortisone acetate, fludrocortisone, tixocortol, medrysone, dexamethasone, dexamethasone acetate, prednisone, prednisolone, prednisolone acetate, fluprednisolone, methylprednisolone, methylprednisolone aceponate, fluorometholone, difluprednate, mazipredone, betamethasone, betamethasone dipropionate, paramethasone, flumethasone, desoximetasone, fluocortolone, diflucortolone, clocortolone, prednylidene, fluprednidene, triamcinolone, triamcinolon acetonide, flunisolide, desonide, prednicarbate, budesonide, fluocinolone
  • the used antimicrobial chemotherapeutics are sampled from the following list:
  • antibacterials (antibiotics, antibacterial/antimycobacterial chemotherapeutics): classes of beta-lactam antibiotics (penicillins, carbapenems, monobactams and/or cephalosporins, carbacephems, oxacephems), macrolides, tetracyclines, aminoglycosides, polypeptides, glycopeptides, lincosamides, lipopeptides, ansamycins, fusidic acid, linezolid, classes of sulfonamides, quinolones, amphenicols, nitrofurans, nitroimidazoles, p-aminosalicylic acid, cycloserine, isoniazid, pyrazinamide, ethionamide, protionamide, ethambutol, clofazimine, dapsone as well as other natural, semisynthetic or synthetic antibacterially effective compounds, which mechanism of action is connected with inhibition of the growth and/
  • antimycotics classes of polyenes, griseofulvin, imidazoles, triazoles, allylamines and other non-azole ergosterol biosynthesis inhibitors, thiocarbamates, glucan synthesis inhibitors (echinocandines, pneumocandines, papulacandines), antimetabolites (flucytosine), ciclopirox, amorolfine and other antifungal effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of fungal pathogens and causes their death.
  • antivirotics classes of pyrimidine and purine nucleotides, reverse transcriptase inhibitors, HIV-protease inhibitors, neuramidase inhibitors, amantadine, interferons, foscarnet as well as other antiviral effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of viral pathogens and causes their death.
  • the subject matter of the invention is the pharmaceutical composition for transdermal application containing anti-inflammatory drugs (non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids) and/or antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics) and simultaneously alaptide as a chemical transdermal penetration modifier.
  • anti-inflammatory drugs non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids) and/or antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics) and simultaneously alaptide as a chemical transdermal penetration modifier.
  • transdermal application alaptide causes an increase or a decrease, in dependence on the used supporting medium (pharmaceutical formulation), in absorption penetration of nonsteroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) to the skin and/or through the skin so that the concentration of the used drug increased at the place of administration, and/or the systemic concentration increased, or it was ensured that drugs act only on the skin surface/in the skin surface layer and do not penetrate to the skin deeper layers or do not have any systemic effects.
  • nonsteroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics anti
  • alaptide as a chemical modifier of transdermal penetration of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics), i.e. as an excipient, is completely unique, and only in this application this possibility of alaptide application is specified for the first time.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/antimycobacterials, antimycotics, antivirotics
  • non-steroidal anti-inflammatory drugs otherwise nonsteroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/antimycobacterials, antimycotics, antivirotics
  • alaptide as the chemical transdermal penetration modifier, which modifies the permeability of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) through the skin and acts as a transdermal penetration enhancer or, by contrast, in dependence on the used pharmaceutical composition, acts as a penetration inhibitor and inhibits systemic effects
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics are convenient both for local/topical and systemic treatment.
  • Their mechanism of action is related to inhibition of the metabolic pathway of arachidonic acid and thus generation of pro-inflammatory substances such as prostacyclins, prostaglandins, thromboxanes and leukotrienes.
  • pro-inflammatory substances such as prostacyclins, prostaglandins, thromboxanes and leukotrienes.
  • pro-inflammatory substances such as prostacyclins, prostaglandins, thromboxanes and leukotrienes.
  • they decrease an elevated temperature, decrease pain perception, act antirheumatically and can have other effects (e.g., increase excretion of uric acid or decrease of platelet agglutination).
  • the antiaggregant effect is used for prevention of acute cerebrovascular accident and myocardial infarction. Due to their antipyretic effect they are used for treatment of various fevers.
  • glucocorticoids are suitable for both local and systemic treatment. Corticoids are indicated for treatment of adults, adolescents as well as children. They express significant anti -inflammatory, anti-edematous and anti -pruritic effect and decrease hyperemia.
  • Systemic treatment can be either substitution therapy - at adrenal insufficiency (prednisone, cortisole) or they can be indicated in specific cases, for example: allergic reactions and illnesses (e.g., bronchial asthma, including status asthmaticus, anaphylactic reactions, including after drug administration, posttransfusion reactions, contact dermatitis, serum sickness, larynx oedema, allergic rhinitis, etc.), autoimmune illnesses (e.g., rheumatoid polyarthritis), haematological illnesses (e.g., leukaemia), infections (e.g., sepsis by G- microbes), prevention of oedema of soft tissues (e.g., brain oedema), organ transplantation (e
  • Corticoids can be used for treatment of inflammatory manifestations and pruritus: eczemas (including atopic and discoid eczemas); dyshidrotic eczema; dermatitis Solaris, prurigo nodularis, psoriasis, neurodermatitis (including lichen simplex), lichen planus, seborrheic dermatitis, contact hypersensitivity manifestations and other dermatitises, lupus erythematodes chronicus discoides, generalized erythroderma, reactions on insect biting and heat rash. They can be indicated at brain oedema, both traumatogenic and connected with expansive process.
  • Corticoids can also be indicated for therapy of aspiration pneumonia together with antibiotics, rheumatoid arthritis, collagenoses, nephrotic syndrome, lymphatic leukaemia, at infections (with appropriate chemotherapy): disseminated or fulminant pulmonary tuberculosis and TB meningitis. Besides, they can be used as a part of treatment of shock states such as hemorrhagic, traumatic or septic shocks. Corticoids can be also used in the therapy of osteoarthrosis, carpal tunnel syndrome, synovitis, irritate arthritis, bursitis, uratic arthritis, epicondylitis, fibrositis and tendovaginitis.
  • Antimicrobial chemotherapeutics are compounds used at present in human and veterinary medicine for growth suppression or elimination of microorganisms (bacteria, yeasts and other fungi and viruses).
  • Antimicrobial chemotherapeutics include antibiotics (compounds of natural origin or semisynthetically modified compounds), antibacterial chemotherapeutics (synthetic compounds), including antituberculotics, antimycotics and antivirotics.
  • Antimicrobial chemotherapeutics are used primarily for treatment of various infectious states but sometimes also for prevention (antibiotic prophylaxis). Often a combination of some antibiotics and antimycotics is used to cover a broad spectrum of microorganisms (e.g., combination of penicillin, streptomycin and amphotericin B).
  • alaptide as a chemical modifier of transdermal penetration of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics), i.e. as an excipient, is completely unique, and only in this application this possibility of alaptide application is specified for the first time.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/ antimycobacterials, antimycotics, antivirotics
  • Alaptide was initially tested as an excipient that influences penetration of different compounds through the skin on the model drug theophylline, which average permeation in combination with micronized alaptide was increased by 65%. After that penetration of ibuprofen through the skin was tested from propylene glycol/water (1:1) medium. The addition of 1% of alaptide (in relation to ibuprofen amount) increased the penetration by 113% within 1 h and by 147% within 2 h. From hydroxypropyl cellulose gel without alaptide addition, max. 0.78% of ibuprofen penetrated through the skin within 2 h.
  • the addition of 1% of alaptide increased the penetration by 177% within 1 h and by 246% within 2 h.
  • the addition of 0.1% of alaptide (in relation to ibuprofen amount) increased the penetration of ibuprofen through the skin from hydroxypropyl cellulose gel by 177% after 30 min and from oleo-cream by 30% more than without alaptide.
  • the penetration of nimesuHde from cream with the addition of 0.1% of alaptide was by 150% higher after 30 min and with the application of 0.1% of nanonized alaptide, by 80% more than from compositions without alaptide.
  • the penetration of meloxicam with the addition of 0.1% of nanonized alaptide was by 383% higher after 30 min than without alaptide.
  • the penetration of acetylsalicylic acid from propylene glycol/water medium with the addition of nanonized alaptide increased by 585% after 30 min, and the penetration of paracetamol with the addition of 0.1% of nanonized alaptide from propylene glycol/water medium was by 1657% higher in 120 min than without alaptide.
  • the penetration of diclofenac with application of 0.1% of alaptide increased by 124% after 30 min and at application of nano-alaptide by 1445% in comparison with the penetration of diclofenac without alaptide.
  • the penetration through the skin of the glucocorticoid budesonide was tested from the propylene glycol/water (1:1) medium, from phosphate buffer (pH 7.4) and from isopropyl myristate without and with the presence of 0.1% of micronized alaptide (in relation to budesonide amount).
  • the permeation of budesonide from the propylene glycol/water medium increased after the addition of alaptide by 480% within 8 h.
  • the penetration of budesonide from the buffer was on the average by 170% more within 20-24 h.
  • budesonide permeation from isopropyl myristate increased on the average by 30% within 6-8 h and by 50% within 20-24 h.
  • Dexamethasone penetration through the skin both from the buffer and the propylene glycol/water medium was possible within 30' min only after the addition of nanonized alaptide.
  • the permeation of dexamethasone acetate with 0.1% amount of micronized alaptide (in relation to dexamethasone acetate amount) from the propylene glycol/water medium increased on the average by 110% within 6-8 h after the addition of alaptide.
  • the amount of dexamethasone acetate penetrated from the buffer after the addition of alaptide was on the average by 190% more within 20-24 h.
  • the permeation of dexamethasone acetate from isopropyl myristate after the addition of alaptide increased on the average by 20% within 20-24 h.
  • Dexamethasone acetate penetration through the skin from carboxymethylcellulose gel with added 0.1% amount of micronized alaptide (in relation to dexamethasone acetate amount) was higher on the average by 10%.
  • fluocinolone was not detectable within 3 h; by contrast, after the addition of nanonized alaptide fluocinolone permeation both from the buffer and the propylene glycol/water medium significantly increased after 30 min; in the case of the propylene glycol/water medium with nanonized alaptide the permeation even increased by 1100% within 1 h.
  • the permeation of fluocinolone acetonide through the skin from the propylene glycol/water medium increased by 180% within 4-8 h and from the buffer by 250% within 8 h. Fluocinolone acetonide penetration from isopropyl myristate increased by 590% within 4 h after the addition of alaptide.
  • hydrocortisone acetate penetrated on the average by 40% more within 20-24 h after the addition of alaptide.
  • Hydrocortisone acetate permeation from isopropyl myristate after the addition of alaptide increased by 40% within 20-24 h than without alaptide.
  • the penetration of prednisolone acetate through the skin from the propylene glycol/water medium increased by 300% within 20-24 h after the addition of alaptide.
  • prednisolone acetate that permeated from the buffer after the addition of alaptide increased on the average by 270% within 4-8 h, and the permeation of prednisolone acetate from isopropyl myristate after the addition of alaptide increased on the average by 30% within 20-24 h.
  • Prednisolone from the buffer with micronized alaptide did not permeate, but from the propylene glycol/water medium with micronized alaptide permeated after 90 min.
  • the permeation of prednisolone from both the buffer and the propylene glycol/water medium significantly increased after 30 min, in the case of the propylene glycol/water medium with nanonized alaptide even by 275% within 3 h.
  • the permeation of prednisone from the propylene glycol/water medium increased by 680% within 4 h
  • the permeation of prednisone from the buffer increased by 650% within 4 h
  • the permeation from isopropyl myristate increased by 320% within 4 h.
  • Triamcinolone did not penetrate through the skin, but the addition of micronized alaptide to the buffer increased the penetration of triamcinolone by 174% after 30 min, and from the propylene glycol/water medium containing the micronized alaptide triamcinolone penetrated by 267% more after 30 min. Without the addition of alaptide triamcinolone acetonide penetrated through the skin from both media in 90 or 120 min. After the addition of micronized alaptide to the buffer, the penetration of triamcinolone acetonide increased by 5% in 90 min.
  • nanonized alaptide to the propylene glycol/water medium enabled the penetration of triamcinolone acetonide already in 30 min, and the addition of micronized alaptide increased the penetration by 790% in 30 min compared to nanonized alaptide. Without the presence of alaptide triamcinolone acetonide from oleo-ointment was not detectable within 3 h, but after the addition of micronized alaptide triamcinolone acetonide was detected already after 30 min. The addition of nanonized alaptide increased the penetration of triamcinolone acetonide through the skin from the oleo-ointment by 273%.
  • triamcinolone acetonide from hydro-cream was not detectable within 3 h.
  • triamcinolone acetonide from the cream was detected already after 90 min and with the addition of nanonized alaptide already after 1 h.
  • the penetration of triamcinolone acetonide from the cream with nanonized alaptide increased by 124% after 90 min in comparison with micronized alaptide.
  • Triamcinolone acetonide from methylcellulose gel without alaptide was not detectable within 3 h, but after the addition of micronized alaptide it was found already after 120 min.
  • nanonized alaptide increased the penetration of triamcinolone acetonide from the gel by 228% i comparison with micronized alaptide.
  • Triamcinolone acetonide from carbomer gel without , alaptide was not . also detectable within 3 h.
  • micronized alaptide triamcinolone acetonide from the gel was detected after 120 min.
  • nanonized alaptide increased the penetration of triamcinolone acetonide from the gel by 5% compared to micronized alaptide.
  • the penetration of amoxicillin through the skin was evaluated from the propylene glycol/water (1:1) medium, from phosphate buffer (pH 7.4) and from isopropyl myristate without and with the presence of 0.1% amount of micronized alaptide (in relation to amoxicillin amount).
  • the permeation of amoxicillin from the propylene glycol/water medium increased after the addition of alaptide by 55% within 8 h and on the average by 92% within 20-24 h.
  • the penetration of amoxicillin from the buffer after the addition of alaptide was on the -average by 106% more within 8 h.
  • the permeation of amoxicillin from isopropyl myristate after the addition of alaptide increased on the average by 5% within 8 h and by 30% within 20-24 h.
  • the addition of alaptide increased the permeation of ampicillin from the propylene glycol/water medium by 145 % within 8 h.
  • On the average the amount of ampicillin that penetrated from the buffer after the addition of alaptide was by 35% more within 8 h.
  • the permeation of ampicillin from isopropyl myristate after the addition of alaptide increased on the average by 54% within 8 h.
  • the permeation of oxacillin from the propylene glycol/water medium increased by 150% within 8 h and on the average by 80% within 20-24 h.
  • the penetration of oxacillin from the buffer was on the average by 27% more within 8 h after the addition of alaptide.
  • the permeation of oxacillin from isopropyl myristate after the addition of alaptide increased on the average by 177% within 8 h.
  • the permeation of benzylpenicillin (penicillin G) from the propylene glycol/water medium increased by 136% within 8 h after the addition of alaptide.
  • the permeation of penicillin G from the buffer after the addition of alaptide was on the average by 16% more within 24 h. Its permeation from isopropyl myristate increased on the average by 5% within 20-24 h after the addition of alaptide.
  • the addition of alaptide increased the permeation of phenoxymethylpenicillin (penicillin V) from the propylene glycol/water medium by 56% within 8 h and on the average by 45% within 20-24 h.
  • the permeation of penicillin V from the buffer after the addition of alaptide was on the average by 43% more within 8 h.
  • the permeation of penicillin V from isopropyl myristate after the addition of alaptide increased on the average by 34% within 8 h.
  • the permeation of ofloxacin from the propylene glycol/water medium after the addition of alaptide increased by 54% within 8 h.
  • the addition of alaptide increased the penetration of ofloxacin from the buffer on the average by 137% within 8 h more and by 85% within 20-24 h.
  • the permeation of ofloxacin from isopropyl myristate after the addition of alaptide increased on the average by 36% within 8 h.
  • the penetration of ofloxacin through the skin from methylcellulose and carbomer gels was also tested without and with the presence of 0.1% of micronized alaptide in time.
  • the penetration of ofloxacin from methylcellulose gel increased after the addition of alaptide on the average by 1040% within 4-8 h and by 136% within 20-24 h.
  • the addition of alaptide increased the penetration of ofloxacin from carbomer gel on the average by 200% within 4-8 h and by 80% within 20-24 h.
  • the penetration of sulfathiazole through the skin from oleo-ointment was tested without and with 0.1% (in relation to sulfathiazole amount) of micronized alaptide or nanonized alaptide in time.
  • the penetration of sulfathiazole from oleo-ointment increased on the average by 10% within 8 h and by 37% within 12-24 h after the addition of micronized alaptide.
  • the penetration of sulfathiazole from oleo-ointment increased on the average by 180% within 8 h and by 330% within 12-24 h after the addition of nanonized alaptide.
  • the penetration of chloramphenicol through the skin from the propylene glycol/water medium and from the buffer was tested without and with 0.1% of micronized alaptide in time.
  • micronized alaptide to the propylene glycol/water medium increased the penetration of chloramphenicol by 7% within 24 h and the addition to the buffer, by 1% within 24 h than without alaptide.
  • the penetration of chloramphenicol through the skin from oleo-ointment was also tested without and with 0.1% (in relation to chloramphenicol amount) of micronized alaptide or nanonized alaptide in time.
  • the penetration of chloramphenicol from the oleo-ointment increased after the addition of micronized alaptide on the average by 90% within 8 h and after the addition of nanonized alaptide on the average by 360% within 8 h and by 1030% within 24 h.
  • the permeation of neomycin sulfate through the skin from the propylene glycol/water medium without and with 0.1% of micronized alaptide was evaluated in time. After the addition of alaptide the permeation of neomycin sulfate increased by 165% after 30 min. The permeation of mupirocin through the skin from hydro-ointment was increased by added 0.1% amount of micronized alaptide by 144% already after 30 min and approx. by 400% after 60 min; thus alaptide significantly accelerated the penetration of mupirocin through the skin.
  • nanonized alaptide significantly inhibited penetration through the skin (decreased the penetration by 60% during the 1 st hour); thus mupirocin will act only on the surface of the skin.
  • the addition of micronized alaptide to the buffer increased the permeation of pyrazinamide from by 63% after 8 h and by 303% after 24 h, and the addition of nanonized alaptide increased the permeation of pyrazinamide by 125% within 24 h.
  • the penetration of pyrazinamide through the skin from carbomer gel was tested without and with the presence of 0.1% (in relation to pyrazinamide amount) of micronized alaptide or nanonized alaptide in time.
  • micronized alaptide to the gel increased the penetration of pyrazinamide by 16% within 24 h
  • nanonized alaptide to the gel increased the penetration of pyrazinamide on the average by 16% within 24 h.
  • the permeation of fluconazole through the skin from the propylene glycol/water medium after the addition of 0.1% of nanonized alaptide increased by 59% within 24 h.
  • the penetration of fluconazole from oleo-ointment after the addition of nanonized alaptide increased on the average by 150% within 8 h and by 350% within 12-24 h.
  • the addition of nanonized alaptide increased the penetration of fluconazole from cream by 28% within 12 h in comparison with the formulation without alaptide.
  • micronized alaptide to the propylene glycol/water medium containing aciclovir caused an increase in the penetration of aciclovir by 114% already after 30 min
  • nanonized alaptide to the propylene glycol/water medium containing aciclovir increased the penetration of aciclovir on the average by 158% after 30 min and by 280% after 2 h.
  • micronized alaptide to the buffer increased the permeation of aciclovir by 126% already after 30 min and by 440% after 2 h.
  • nanonized alaptide increased the penetration of aciclovir through the skin from hydro-cream by 25% already after 30 min
  • micronized alaptide increased the penetration of aciclovir from carbomer gel on the average by 37% after 30 min.
  • the particle size distribution of the used micronized alaptide was 50-80% up to 10 maxium Feret diameters. It was measured by a microscope NIKON Optiphot 2 with a digital camera VDS CCD-1300F.
  • the used nanonized alaptide was prepared using a nanomill NETZSCH with glass beads.
  • the particle size of nanonized alaptide was measured using Sympatec NANOPHOX equipment, and the particle size x 5 o- 9 0 was up to 900 nm.
  • Alaptide as the excipient affecting the penetration of drugs to/through the skin can be combined in pharmaceutical formulations with the following non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs): phenylbutazone, oxyphenbutazone, kebuzone, tribuzone, sulfinpyrazone, azapropazone, mofebutazone, clofezon, suxibuzone, flufenamic acid, niflumic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, aclantate, etofenamate, flunixine, ibufenac, alclofenac, diclofenac, indometacin, acemetacin, tropesin, sulindac, lonazolac, tolmetin, ketorolac, nabumetone, fenbumetone, indobufene, z
  • Alaptide can be also combined in pharmaceutical formulations with the following antipyretics/non-opiate analgesics: paracetamol, bucetin, propacetamol, salicylic acid, acetylsalicylic acid, choline salicylate, lysine salicylate, salicylate sodium or potassium, imidazole salicylate, morpholine salicylate, salsalate, ethenzamide, guacetisal, carbasalate calcium, salicylamide, methylsalicylate, aloxiprin, lysine acetylsalicylate, benorilate, gentisic acid, dipyrocetyl, diflunisal, phenazone, aminophenazone, propyphenazone, ramiphenazone, metamizole, rimazoline, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide, menthol, n
  • Alaptide can be also combined in pharmaceutical formulations with the following glucocorticoids: hydrocortisone, hydrocortisone acetate, fludrocortisone, tixocortol, medrysone, dexamethasone, dexamethasone acetate, prednisone, prednisolone, prednisolone acetate, fluprednisolone, methylprednisolone, methylprednisolone aceponate, fluorometholone, difluprednate, mazipredone, betamethasone, betamethasone dipropionate, paramethasone, flumethasone, desoximetasone, fluocortolone, diflucortolone, clocortolone, prednylidene,- fluprednidene, triamcinolone, triamcinolon acetonide, flunisolide, desonide, prednicarbate, ⁇ budeson
  • Alaptide can be also combined in pharmaceutical formulations with the following antimicrobial chemotherapeutics: ⁇ ' ' ' ' ' antibacterials:- (antibiotics, antibacterial/antimycobaeterial chemotherapeutics): classes of beta-lactam antibiotics- (penicillins, carbapenems, monobactams - and/or cephalosporins, carbacephems, oxacephems), macrolides, tetracyclines, aminoglycosides, polypeptides, glycopeptides, lincosamides, lipopeptides, ansamycins, fusidic acid, linezolid, classes of sulfonamides, qiiinolones, amphenicols, nitrofurans, nitroimidazoles, ⁇ -aminosalicylic acid, cycloseriiie, isoniazid, pyrazinamide, ethionamide, protionamide,
  • aritimvcotics class of polyenes, griseofulvin, imidazoles, triazoles, allylamines and other non- azole ergosterol biosynthesis inhibitors, thiocarbamates, glucan synthesis inhibitors (eehinocandines, pneumocandines, papulacandines), antimetabolites (flucytosine), ciclopirox, amorolfine and other antifungal effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of fungal pathogens and causes their death.
  • antivirotics class of pyrimidine and purine nucleotides, reverse transcriptase inhibitors, HIV- protease inhibitors, neuramidase inhibitors, amantadine, interferons and foscarnet as well as other antiviral effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of viral pathogens and causes their death.
  • the subject matter of the invention is the original pharmaceutical compositions for human and/or veterinary applications that are characterized by the combination of alaptide as an excipient with non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics in ointment, cream, gel or a transdermal therapeutic system, where alaptide modifies the permeability of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) arid/or antipyretics/non-opiate analgesics through the skin and effects as a transdermal penetration modifier.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • NSAIDs antipyretics/non-opiate analgesics
  • non-steroidal anti-inflammatory drugs can be used: phenylbutazone, oxyphenbutazone, kebuzone, tribuzone, sulfinpyrazone, azapropazone, mofebutazone, clofezon, suxibuzone, flufenamic acid, niflumic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, aclantate, etofenamate, flunixine, ibufenac, alclofenac, diclofenac, indometacin, acemetacin, tropesin, sulindac, lonazolac, tolmetin, ketorolac, nabumetone, fenbumetone, indobufene, zomepirac, bumadizone, etodolac, fentiazac, flufenamic acid, niflumic acid, mefenamic acid,
  • antipyretics/non-opiate analgesics can be used: paracetamol, bucetin, propacetamol, salicylic acid, acetylsalicylic acid, choline salicylate, lysine salicylate, salicylate sodium or potassium, imidazole salicylate, morpholine salicylate, salsalate, ethenzamide, guacetisal, carbasalate calcium, salicylamide, methylsalicylate, aloxiprin, lysine acetylsalicylate, benorilate, gentisic acid, dipyrocetyl, diflunisal, phenazone, aminophenazone, propyphenazone, ramiphenazone, metamizole, rimazoline, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide, menthol, nabiximols, other antipyretic
  • compositions for human and/or veterinary applications that are characterized by the combination of alaptide as an excipient and glucocorticoids in ointment, cream, gel or a transdermal therapeutic system, where alaptide modifies the permeability of glucocorticoids through the skin and acts as a transdermal penetration modifier.
  • glucocorticoids can be used: hydrocortisone, hydrocortisone acetate, fludrocortisone, tixocortol, medrysone, dexamethasone, dexamethasone acetate, prednisone, prednisolone, prednisolone acetate, fluprednisolone, methylprednisolone, methylprednisolone aceponate, fluorometholone, difluprednate, mazipredone, ⁇ betamethasone, betamethasone dipropionate, paramethasone, flumethasone, desoxirrietasone, fluocortolone, diflucortolone, clocortolone, prednylidene, fluprednidene, triamcinolone, triamcinolon acetonide, flunisolide, desonide, prednicarbate, budesonide, fluocinolone ace
  • compositions for. human and/or veterinary applications that are characterized by the combination of alaptide as an excipient and antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) in ointment, cream, gel or a transdermal therapeutic system, where alaptide modifies the permeability of antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics) through the skin and acts as a transdermal penetration modifier.
  • alaptide modifies the permeability of antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics) through the skin and acts as a transdermal penetration modifier.
  • glucocorticoids can be used:
  • antibacterials (antibiotics, antibacterial/antimycobacterial chemotherapeutics): classes of beta-lactam antibiotics (penicillins, carbapenems, monobactams and/or cephalosporins, carbacephems, oxacephems), macrolides, tetracyclines, aminoglycosides, polypeptides, glycopeptides, lincosamides, lipopeptides, ansamycins, fusidic acid, linezolid, classes of sulfonamides, quinolones, amphenicols, nitrofurans, nitroimidazoles, ⁇ -aminosalicylic acid, cycloserine, isoniazid, pyrazinamide, ethionamide, protionamide, ethambutol, clofazimine, dapsone as well as other natural, semisynthetic or synthetic antibacterially effective compounds, which mechanism of action is connected with inhibition of the growth and/
  • antimycotics class of polyenes, griseofulvin, imidazoles, triazoles, allylamines and other non- azole ergosterol biosynthesis inhibitors, thiocarbamates, glucan synthesis inhibitors (echinocandines, pneumocandines, papulacandines), antimetabolites (flucytosine), ciclopirox, amorolfine and other antifungal effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of fungal pathogens and causes their death.
  • antivirotics class of pyrimidine and purine nucleotides, reverse transcriptase inhibitors, HIV- protease inhibitors, neuramidase inhibitors, amantadine, interferons and foscarnet as well as other antiviral effective compounds, which mechanism of action is connected with inhibition of the growth and/or multiplication of viral pathogens and causes their death.
  • Alaptide alone is poorly soluble; its solubility in water is 0.1104 g/100 mL, in ethanol 0.1011 g/100 mL and in the mixture watenethanol 1: 1 0.3601 g/100 mL; its log Pw/oa is 1.39.
  • Alaptide can be effectively dissolved in aqueous solutions containing surfactants such as Tween 20, Tween 80, Macrogol 4000, Macrogol 6000, propylene glycol, sodium lauryl sulfate, poloxamer (Pluronic), castor oil polyethylene glycol ether (Cremophor EL) or various PEG-derivatives (PEG-stearates, PEG-esters of fatty acids, PEG-derivatives of fatty acid glycerides, PEG-D-a-tocoferole) or complexing compounds such as cyclodextrins and their derivatives (e.g., hydroxypropyl-P-cyclodextrin), dextrans and their derivatives, pectins and their salts and derivatives, glucans and their derivatives, chitosan and its derivatives, methylcellulose and its salts and derivatives.
  • surfactants such as Tween 20, Tween 80, Macrogol 4
  • Complexes/adducts can be prepared by mixing aqueous solutions of surfactants or complexing agents with alaptide. After completion of mixing a complex/adduct can be used for preparation of pharmaceutical compositions (formulations), or the solvent can be evaporated, and the obtained evaporation solid residue (a product of complexation) can be consequently used for the preparation of pharmaceutical compositions (formulations).
  • alaptide can be applied alone or together with other excipients or a combination of excipients that increase its solubility in ointment, cream, gel or a transdermal therapeutic system.
  • Alaptide can be used in the concentration from 0.001 to 5% as a chemical transdermal penetration enhancer that supports an increase in absorption/penetration of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) to the skin and/or through the skin, increasing their concentration at the place of administration and/or their systemic concentration.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • Alaptide nanoparticles can be obtained by milling alaptide with emulsifiers and other stabilizers. Alaptide nanoparticles were generated by dispergation using a technique of wet milling in the aqueous solution of a surface modifier. The suspension generated in this manner is milled using a ball mill in the presence of a milling medium. This method assumes pulverization of all major micrometer particles to nanoparticles.
  • deoxycholate sodium, sodium lauryl sulfate, poloxamer, povidone, Macrogol 6000 can be used as wetting agents. Grinding balls can be polystyrene, ceramic or glass.
  • Modified alaptide was obtained by the above-mentioned routes and showed considerably higher solubility and modified physico-chemical properties depending on modification, thus optimized for the particular composition of ointment (oleo-ointment, hydro-ointment), cream (oleo-cream, hydro-cream), gel or a transdermal therapeutic system.
  • Alaptide alone (micronized alaptide) or nanonized alaptide or alaptide complexes/adducts can be used as pharmaceutical adjutants (excipients) for pharmaceutical compositions (formulations) designed for humane and/or veterinary applications.
  • alaptide serves as a chemical transdermal penetration modifier that influences the absorption/penetration of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/antimycobacterials, antimycotics, antivirotics) to the skin and/or through the skin, increasing their concentration at the place of administration and/or their systemic concentration.
  • non-steroidal anti-inflammatory drugs otherwise non-steroidal antiphlogistics or NSAIDs
  • antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics antibacterials/antimycobacterials, antimycotics, antivirotics
  • semisolid formulations can be generally divided into oleo-/hydro- ointments, oleo-/hydro-creams and gels.
  • Untreated, surface-modified and nanonized alaptide was added to ointment, cream and gel bases in the amount ranged from 0.1% to 5% of the total composition of formulation.
  • mixtures of low- and high-molecular macrogols e.g., 300 and 1500 (1: 1), can be used as excipients.
  • Example of the composition of oleo-ointment with alaptide 0.01 to 100 % w/w (in relation to drug) and 1 to 10% of drug can be as follows: alaptide from 0.001 to 10 g, drug from 1 to 10 g, cera lanae hydrosa from 65 to 75 g, yellow vaseline from 10 to 20 g, liquid paraffin up to 100 g. (i.e. ointment base for antibiotics).
  • Example of the composition of hydro-ointment with alaptide 0.01 to 100 % w/w (in relation to drug) and 1 to 10% of drug can be as follows: alaptide from 0.001 to 10 g, drug from 1 to 10 g, macrogol up to 100 g.
  • Example of the composition of oleo-cream with alaptide 0.01 to 100 % w/w (in relation to drug) and 1 to 10% of drug can be as follows: alaptide from 0.001 to 10 g, drug from 1 to 10 g, Synderman ® from 80 to 95 g, propylene glycol up to 100 g.
  • Example of the composition of hydro-cream with alaptide 0.01 to 100 % w/w (in relation to drug) and 1 to 10% of drug can be as follows: alaptide from 0.001 to 10 g, drug from 1 to 10 g, Cremor Neo-Aquasorbi ® from 80 to 95 g, propylene glycol up to 100 g.
  • Example of the composition of gel with alaptide 0.01 to 100 % w/w (in relation to drug) and 1 to 10% of drug can be as follows: alaptide from 0.001 to 10 g, drug from 1 to 10 g, Carboxymethylcellulose ointment (carboxymethylcellulose sodium 5 g, Macro gol 300 10 g, propylene glycol 2.5 g, methylparaben 0.2 g, propylparaben 0.2 g, purified water 87.3 g) up to 100 g.
  • the particle size distribution of the used micronized alaptide was 50-80% up to 10 maxium Feret diameters. It was measured by a microscope NIKON Optiphot 2 with a digital camera VDS CCD-1300F.
  • the used nanonized alaptide was prepared using a nanomill NETZSCH with glass beads.
  • the particle size of the used nanonized alaptide was measured by NANOPHOX (0138 P) Sympatec equipment, and the particle size x 50 -X9 0 was up to 900 nm.
  • Fig. 1 Influencing biotransformation enzymes CYP1A1, CYP1A2 and CYP1B1 in hepatocytes.
  • Fig. 2 Penetration of theophylline (TEO) through the skin from water depending on the amount of micronized alaptide (ALA) in time. Of the original amount of TEO, max. 0.24% penetrated without the addition of ALA within 1 h. The addition of 1 mg ALA did not have any significant effect on TEO permeation, but the addition of 10 mg of ALA increased permeation through the skin approx. 1.5 times within 1 h and approx. 1.7 times within 2 h. After 24 h the effect of higher ALA amount was not apparent.
  • TEO micronized alaptide
  • Fig. 3 Penetration of theophylline (TEO) through the skin from the phosphate buffer
  • Fig. 4 Penetration of theophylline (TEO) through the skin from the propylene glycol
  • PG water/water (1: 1) medium depending on the amount of micronized alaptide (ALA) in time.
  • ALA micronized alaptide
  • the addition of 1 mg of ALA to the system increased the penetration of TEO by 35% within 2 h, but then penetration decreased and after 24 h it was higher only by 10%.
  • the addition of 10 mg of ALA to the system increased the average penetration by approx. 180% within 1 h, and then the penetration decreased again.
  • Fig. 5 Penetration of ibuprofen (IBU) through the skin from the propylene glycol
  • PG water/water (1:1) medium depending on the amount of micronized alaptide (ALA) in concentrations 0.1%, 1%, 10%.
  • ALA micronized alaptide
  • the further addition of ALA up to 100 mg (10%) of ALA decreased the penetration of IBU.
  • Fig. 6 Penetration of ibuprofen (IBU) through the skin from hydroxypropyl cellulose gel depending on the amount of micronized alaptide (ALA) in time.
  • IBU ibuprofen
  • the hydroxypropyl cellulose gel with 1% of IBU was prepared, and micronized alaptide (ALA) in concentrations 0.1%, 1%, 10% was added.
  • max. 0.78% penetrated without ALA within 2 h.
  • the highest penetration was detected after the addition of 10 mg (1%) of ALA; the permeation was increased by 177% within 1 h and by 246% within 2 h.
  • the further addition of ALA up to 100 mg (10%) increased IBU penetration by 74% within 2 h.
  • Fig. 7 Comparison of the penetration of ibuprofen (IBU) through the skin from various media without and with the presence of 0.1% (in relation to IBU amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1: 1) medium, from hydroxypropyl cellulose gel and from oleo-cream.
  • ALA micronized alaptide
  • Fig. 8 Comparison of the penetration of nimesulide (NEVI) through the skin from various media without and with the presence of 0.1% (in relation to NIM amount) of micronized or nanonized alaptide (ALA, NALA) in time: from buffer (pH 7.4) and from oleo-cream.
  • ALA micronized or nanonized alaptide
  • Fig. 9 Comparison of the penetration of meloxicam (MEL) through the skin from buffer
  • Fig. 10 Comparison of the penetration of acetylsalicylic acid (ASA) through the skin from buffer (pH 7.4) or from the propylene glycol (PG)/water (1: 1) medium without and with the presence of 0.1% (in relation to ASA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • ASA acetylsalicylic acid
  • PG propylene glycol
  • NALA micronized or nanonized alaptide
  • Fig. 11 Comparison of the penetration of paracetamol (PAR) through the skin from buffer
  • Fig. 12 Comparison of the penetration of diclofenac (DIC) through the skin from buffer
  • Fig. 13 Comparison of the penetration of diclofenac (DIC) through the skin from carbomer gel without and with the presence of 0.1% (in relation to DIC amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • DIC diclofenac
  • ALA micronized or nanonized alaptide
  • NALA micronized or nanonized alaptide
  • Fig. 14 Comparison of the penetration of diclofenac (DIC) through the skin from hydroxypropyl cellulose gel without and with the presence of 0.1% (in relation to DIC amount) of micronized alaptide (ALA) in time.
  • DIC diclofenac
  • ALA micronized alaptide
  • Fig. 15 Comparison of the penetration of diclofenac (DIC) through the skin from hydro- ointment without and with the presence of 0.1% (in relation to DIC amount) of micronized alaptide (ALA) in time.
  • DIC diclofenac
  • ALA micronized alaptide
  • Fig. 16 Comparison of the penetration of budesonide (BUD) through the skin from various media without and with the presence of 0.1% (in relation to BUD amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1:1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM). Without the addition of ALA BUD (lO mg/mL, 100%) was detectable in 6 h or 8 h, but with added ALA already after 4 h or 6 h. The penetration of BUD from the PG/water medium after the addition of ALA increased by 480% within 8 h and on the average by 210% within 20-24 h.
  • ALA micronized alaptide
  • the penetration of BUD from the buffer after the addition of ALA was on the average by 170 % higher within 20-24 h.
  • the permeation of BUD from isopropyl myristate after the addition of ALA increased on the average by 30% within 6-8 h and by 50% within 20-24 h.
  • Fig. 17 Comparison of the penetration of dexamethasone (DEX) through the skin from various media without and with the presence of 0.1% (in relation to DEX amount) of micronized or nanonized alaptide (ALA, NALA) in time: DEX from the propylene glycol (PG)/water (1:1) medium and from buffer (pH 7.4). Without the addition of ALA DEX (10 mg/mL, 100 %) penetrated from neither of the media. After the addition of ALA DEX was detected within 3 h from both media, and after the addition of NALA DEX significantly penetrated within 30 min.
  • DEX dexamethasone
  • Fig. 19 Comparison of the penetration of fluocinolone (FLC) through the skin from various media without and with the presence of 0.1% (in relation to FLC amount) of micronized or nanonized alaptide (ALA, NALA) in time: from the propylene glycol (PG)/water (1: 1) medium and from buffer (pH 7.4).
  • FLC 10 mg mL, 100%
  • ALA FLC was not found from the buffer, but from the PG/water medium it was found within 30 min, and after the addition of NALA FLC significantly penetrated from both media within 30 min, in the case of the PG/water medium on the average by 1100% within 1 h.
  • Fig. 20 Comparison of the penetration of fluocinolone-acetonide (FLA) through the skin from various media without and with the presence of 0.1% (in relation to FLA amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/ water (1:1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • FLA fluocinolone-acetonide
  • ALA micronized alaptide
  • IPM isopropyl myristate
  • Fig. 21 Comparison of the penetration of hydrocortisone acetate (HKA) through the skin from various media without and with the presence of 0.1% (in relation to HKA amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1:1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • PG propylene glycol
  • IPM isopropyl myristate
  • HKA 10 mg/mL, 100%
  • the penetration of HKA from the buffer and from isopropyl myristate after the addition of ALA increased on the average by 40% within 20-24 h.
  • Fig. 22 Comparison of the penetration of prednisolone acetate (PLA) through the skin from various media without and with the presence of 0.1% (in relation to PLA amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1:1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • ALA PLA micronized alaptide
  • PG propylene glycol
  • IPM isopropyl myristate
  • Fig. 23 Comparison of the penetration of prednisolone (PDL) through the skin from various media without and with the presence of 0.1% (in relation to PDL amount) of micronized or nanonized alaptide (ALA, NALA) in time: from the propylene glycol (PG)/water (1: 1) medium and from buffer (pH 7.4).
  • ALA PDL 10 mg/mL, 100%
  • PG/water medium 1: 1 medium
  • buffer pH 7.4
  • Fig. 24 Comparison of the penetration of prednisone (PDN) through the skin from various media without and with the presence of 0.1% (in relation to PDN amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1: 1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • ALA PDN lO mg/ml, 100%
  • IPM isopropyl myristate
  • Fig. 25 Comparison of the penetration of triamcinolone (TRO) through the skin from various media without and with the presence of 0.1% (in relation to TRO amount) of micronized or nanonized alaptide (ALA, NALA) in time: from the propylene glycol (PG)/water (1:1) medium and from buffer (pH 7.4).
  • ALA micronized or nanonized alaptide
  • PG propylene glycol
  • buffer pH 7.4
  • Fig. 26 Comparison of the penetration of triamcinolone acetonide (TRA) through the skin from various media without and with the presence of 0.1% (in relation to TRA amount) of micronized or nanonized alaptide (ALA, NALA) in time: from the propylene glycol (PG)/water (1: 1) medium and from buffer (pH 7.4). Without the addition of ALA TRA (10 mg/mL, 100 %) penetrated from both media after 90 min or 120 min. After the addition of ALA to the buffer the penetration of TRA increased by 5% within 90 min. The addition of NALA to the PG/water medium caused the penetration of TRA already in 30 min. The addition of ALA to the PG/water medium increased the penetration of TRA in comparison with NALA by 790% in 30 min.
  • TRA triamcinolone acetonide
  • Fig. 27 Comparison of the penetration of dexamethasone acetate (DEA) through the skin from gel without and with the presence of 0.1% (in relation to DEA amount) of micronized alaptide (ALA) in time: DEA penetrated from the formulation without and with the addition of ALA after 20 h, nevertheless the addition of ALA increased the penetration of DEA on the average by 10%.
  • DEA dexamethasone acetate
  • ALA micronized alaptide
  • Fig. 28 Comparison of the penetration of fluocinolone acetonide (FLA) through the skin from hydro-cream, oleo-cream and ointment without and with the presence of 0.1% (in relation to FLA amount) of micronized alaptide (ALA) in time: the highest penetration of FLA was observed from the oleo-cream, the penetration from the hydro-cream was on the average by 14% less and from the ointment by almost 96% less. The penetration of FLA from the hydro-cream with added ALA increased on the average by 260% within 4-8 h and by 110% within 20-24 h.
  • FLA fluocinolone acetonide
  • ALA micronized alaptide
  • the penetration of FLA from the oleo-cream with added ALA increased on the average by 230% within 4-8 h and by 160% within 20-24 h.
  • the penetration of FLA from the ointment with added ALA increased on the average by 20% within 20-24 h.
  • Fig. 29 Comparison of the penetration of triamcinolone acetonide (TRA) through the skin from oleo-ointment without and with the presence of 0.1% (in relation to TRA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • TRA triamcinolone acetonide
  • ALA micronized or nanonized alaptide
  • TRA from the formulation without ALA/NALA was not found within 3 h. After the addition of ALA TRA was found already within 30 min, and the addition of NALA increased the penetration of TRA by 273%.
  • Fig. 30 Comparison of the penetration of triamcinolone acetonide (TRA) through the skin from hydro-cream without and with the presence of 0.1% (in relation to TRA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • TRA triamcinolone acetonide
  • ALA micronized or nanonized alaptide
  • TRA from the formulation without ALA/NALA was not found within 3 h.
  • ALA TRA was found already after 90 min.
  • NALA TRA was fou d within 1 h, and within 90 miri the penetration of - TRA with the addition of NALA increased by 124% in comparison with ALA.
  • Fig. 31 Comparison of the penetration of triamcinolone acetonide (TRA) through the skin from methylcellulose gel without and with the presence of 0.1% (in relation to TRA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • TRA triamcinolone acetonide
  • ALA micronized or nanonized alaptide
  • TRA from the formulation without ALA/NALA was not found within 3 h. After the addition of ALA TRA was found already after 120 min. The penetration of TRA with the addition of NALA was increased by 228% in comparison with ALA.
  • Fig. 32 Comparison of the penetration of triamcinolone acetonide (TRA) through the skin from carbomer gel without and with the presence of 0.1% (in relation to TRA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • TRA triamcinolone acetonide
  • ALA micronized or nanonized alaptide
  • TRA from formulation without ALA NALA was not found within 3 h. After the addition of ALA TRA was found already within 120 min. The addition of NALA increased the penetration of TRA by 5% in comparison with ALA.
  • Fig. 33 Comparison of the penetration of amoxicillin (AMX) through the skin from various media without and with the presence of 0.1% (in relation to AMX amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1: 1) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • the penetration of AMX (10 mg/mL, 100%) from the PG/water medium after the addition of ALA increased by 55% within 8 h and on the average by 92% without 20-24 h.
  • the addition of ALA increased the penetration of AMX from the buffer on the average by 106% within 8 h.
  • the penetration of AMX from isopropyl myristate with ALA increased on the average by 5% within 8 h and by 30% within 20-24 h.
  • Fig. 34 Comparison of the penetration of ampicillin (AMP) through the skin from various media without and with the presence of 0.1% (in relation to AMP amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1: 1) medium, from buffer (pH 7.4) and from isopropyl myristate ( ⁇ ).
  • the penetration of AMP (10 mg/mL, 100%) from the PG/water medium after the addition of ALA was increased by 145% within 8 h.
  • the addition of ALA increased the penetration of AMP from the buffer on the average by 35% within 8 h.
  • the addition of ALA increased the penetration of AMP from isopropyl myristate on the average by 54% within 8 h.
  • Fig. 35 Comparison of the penetration of oxacillin (OXL) through the skin from various- media without and with the presence of 0.1% (in relation to OXL amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1: 1) medium, from buffer (pH 7.4) and from isopropyl myristate ( ⁇ ).
  • the penetration of OXL (10 mg/mL, 100%) from the PG/water medium after the addition of ALA increased by 150% within 8 h and on the average by 80% within 20-24 h.
  • the addition of ALA increased the penetration of OXL from the buffer on the average by 27% within 24 h.
  • the addition of ALA increased the penetration of OXL from isopropyl myristate on the average by 177% within 8 h.
  • Fig. 36 Comparison of the penetration of benzylpenicillin (penicillin G, PEG) through the skin from various media without and with the presence of 0.1% (in relation to PEG amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1:1) medium, from buffer (pH 7.4) and from isopropyl myristate ( ⁇ ).
  • the penetration of PEG (10 mg/mL, 100%) from the PG/water medium after the addition of ALA was increased by 136% within 8 h.
  • the addition of ALA increased the penetration of PEG from the buffer on the average by 16% within 24 h and from isopropyl myristate on the average by 5% within 20-24 h.
  • Fig. 36 Comparison of the penetration of benzylpenicillin (penicillin G, PEG) through the skin from various media without and with the presence of 0.1% (in relation to PEG amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/
  • Fig. 38 Comparison of the penetration of ofloxacin (OFX) through the skin from various media without and with the presence of 0.1% (in relation to OFX amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water ' (l: l) medium, from buffer (pH 7.4) and from isopropyl myristate (IPM).
  • the penetration of OFX (10 mg/mL, 100%) from the PG/water medium after the addition of ALA was increased by 54% within 8 h.
  • the addition of ALA increased the penetration of OFX from the buffer on the average by 137% within 8 h and by 85% within 20-24 h and from isopropyl myristate on the average by 36% within 8 h.
  • Fig. 39 Comparison of the penetration of ofloxacin (OFX) through the skin from methylcellulose and carbomer gel without and with the presence of 0.1% (in relation to OFX amount) of micronized alaptide (ALA) in time.
  • the penetration of OFX from the methylcellulose gel after the addition of ALA increased on the average by 1040% within 4-8 h and by 136% within 20-24 h.
  • the addition of ALA increased the penetration of OFX from the carbomer gel on the average by 200% within 4-8 h and by 80 % within 20-24 h.
  • Fig. 40 Comparison of the penetration of sulfafhiazole (SFT) through the skin from oleo- ointment without and with the presence of 0.1% (in relation to SFT amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • SFT sulfafhiazole
  • ALA micronized or nanonized alaptide
  • the penetration of SFT from the formulation after the addition of ALA increased on the average by 10% within 8 h and by 37% within 12-24 h.
  • the addition of NALA increased the penetration of SFT on the average by 180% within 8 h and by 330% within 12- ⁇ 24 h.
  • Fig. 41 Comparison of the penetration of chloramphenicol (CRF) through the skin from various media without and with the presence of 0.1% (in relation to CRF amount) of micronized alaptide (ALA) in time: from the propylene glycol (PG)/water (1 : 1) medium and from buffer (pH 7.4). After the addition of ALA the penetration of CRF (10 mg/mL, 100%) from the PG/water medium was increased by 7% within 24 h and from the buffer by 1% within 24 h.
  • CRF chloramphenicol
  • Fig. 42 Comparison of the penetration of chloramphenicol (CRF) through the skin from oleo-ointment without and with the presence of 0.1% (in relation to CRF amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • CRF chloramphenicol
  • the penetration of CRF from the formulation after the addition of ALA increased on the average by 90% within 8 h.
  • the penetration of CRF from the formulation after the addition of NALA increased on the average by 360% within 8 h and by 1030% within 24 h.
  • Fig. 43 Comparison of the penetration of neomycin sulphate (NMC) through the skin from the propylene glycol (PG)/water (1: 1) medium without and with the presence of 0.1% (in relation to NMC amount) of micronized alaptide (ALA).
  • NMC neomycin sulphate
  • PG propylene glycol
  • ALA micronized alaptide
  • Fig. 44 Comparison of the penetration of mupirocin (MPC) through the skin from hydro- ointment without and with the presence of 0.1% (in relation to MPC amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • MPC micronized or nanonized alaptide
  • ALA micronized or nanonized alaptide
  • Fig. 45 Comparison of the penetration of pyrazinamide (PZA) through the skin from buffer
  • Fig. 46 Comparison of the penetration of pyrazinamide (PZA) through the skin from carbomer gel without and with the presence of 0.1% (in relation to PZA amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • PZA pyrazinamide
  • ALA micronized or nanonized alaptide
  • the addition of ALA increased the penetration of PZA (10 mg/mL, 100 %) from the gel by 16% within 24 h
  • NALA micronized or nanonized alaptide
  • Fig. 47 Comparison of the penetration of fluconazole (FLU) through the skin from the propylene glycol (PG)/water (1: 1) medium without and with the presence of 0.1% (in relation to FLU amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • FLU fluconazole
  • Fig. 48 Comparison of the penetration of fluconazole (FLU) through the skin from oleo- ointment and hydro-cream without and with the presence of 0.1% (in relation to FLU amount) of nanonized alaptide (NALA) in time.
  • FLU fluconazole
  • NALA nanonized alaptide
  • Fig. 49 Comparison of the penetration of aciclovir (ACL) through the skin from various media without and with the presence of 0.1% (in relation to ACL amount) of micronized or nanonized alaptide (ALA, NALA) in time: from the propylene glycol (PG)/watef (1:1) medium and from buffer (pH 7.4).
  • ALA micronized or nanonized alaptide
  • PG propylene glycol
  • buffer pH 7.4
  • Fig. 50 Comparison of the penetration of aciclovir (ACL) through the skin from hydro- cream or carbomer gel without and with the presence of 0.1% (in relation to ACL amount) of micronized or nanonized alaptide (ALA, NALA) in time.
  • ACL aciclovir
  • NALA micronized or nanonized alaptide
  • the rotor speed was increased to 1500 rpm after 6 h of milling.
  • the total time of milling was 57.5 h.
  • the content of alaptide in the suspension was 38.76 g/L (determined by RP-HPLC).
  • the drug itself active pharmaceutical ingredient
  • the drug in formulation with various concentrations of micronized or nanonized alaptide nanonized alaptide in the amount corresponding to the concentration of micronized alaptide
  • the skin was mounted with the epidermal side up between the donor and the receptor compartments of the diffusion cell.
  • the receptor compartment (volume 5.2 mL) was filled with phosphate buffered saline (pH 7.4), with a mixture of propylene glycol: water (1: 1) or with isopropyl myristate and maintained at 37+0.5 °C using a circulating water bath.
  • the receptor compartment was continuously stirred using a magnetic stirring bar (800 rpm). Than a sample was applied to the skin surface, and the donor compartment of the cell was covered by Parafilm ® . Samples (0.5 mL) were taken from the receptor phase in time intervals, and the cell was refilled with an equivalent volume of the fresh buffer, the mixture of propylene glycol:water (1: 1) or isopropyl myristate solution. For each compound, a minimum of three determinations were performed using skin fragments from a minimum of 2 animals.
  • the penetration through the skin of the drug alone or the drug in formulation without alaptide was monitored, then the penetration of the drug with various concentrations of micronized or nanonized alaptide (nanonized alaptide in the amount corresponding to the concentration of micronized alaptide) was monitored. Also the penetration of the drug from the particular pharmaceutical composition (ointment, cream, gel) with various concentrations of micronized or nanonized alaptide (nanonized alaptide in the amount corresponding to the concentration of micronized alaptide) was monitored. The concentration of the penetrated drug was determined by RP-HPLC method with UV-VIS detection.
  • a drug ibuprofen, diclofenac, meloxicam, nimesulide, fluocinolone acetonide, fluconazole, aciclovir
  • ointment containing from 0.001 to 10 g, otherwise from 0.01 to 100% (w/w in relation to the drug amount) of micronized alaptide or nanonized alaptide (in the amount corresponding to the concentration of micronized alaptide) and a drug (ibuprofen, diclofenac, meloxicam, nimesulide, fluocinolone acetonide, sulfathiazole, chloramphenicol, mupirocin, fluconazole, aciclovir) was prepared, and permeation experiments were performed according to Example 2.
  • a drug ibuprofen, diclofenac, meloxicam, nimesulide, fluocinolone acetonide, sulfathiazole, chloramphenicol, mupirocin, fluconazole, aciclovir

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Abstract

L'invention concerne la manière d'utiliser de l'alaptide micronisé, nanonisé et/ou modifié en surface, qui affecte la pénétration d'autres composés pharmaceutiquement actifs à travers la peau en tant qu'adjuvant pharmaceutique (excipient). Ces compositions pharmaceutiques composées d'alaptide en tant qu'excipient, d'ingrédients pharmaceutiquement actifs (des médicaments anti-inflammatoires non stéroïdiens et/ou des antipyrétiques/des analgésiques non opiacés et/ou des glucocorticoïdes et/ou des agents chimiothérapeutiques antimicrobiens, c'est-à-dire des antibactériens, des antimycotiques, des antiviraux) et autres excipients pharmaceutiques peuvent être utilisés pour la préparation de formulations de médicaments, qui peuvent influencer le taux de médicament dans le corps au cours du temps et peuvent être utilisés à la fois pour une administration locale et une administration systémique.
PCT/CZ2012/000073 2011-08-11 2012-08-02 Utilisation d'alaptide en tant que modificateur de pénétration transdermique dans des compositions pharmaceutiques pour des applications humaines et vétérinaires contenant des médicaments anti-inflammatoires et/ou des agents chimiothérapeutiques antimicrobiens WO2013020527A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CZ2011-495 2011-08-11
CZ2011-495A CZ304915B6 (cs) 2011-08-11 2011-08-11 Využití alaptidu jako modifikátoru transdermální penetrace ve farmaceutických kompozicích pro humánní a veterinární aplikace obsahující nesteroidní antiflogistika a/nebo antipyretika-analgetika
CZ2012-72 2012-02-01
CZ2012-72A CZ306770B6 (cs) 2012-02-01 2012-02-01 Použití alaptidu jako modifikátoru transdermální penetrace ve farmaceutických kompozicích pro humánní a veterinární aplikace obsahující glukokortikoidy
CZ2012-511 2012-07-26
CZ2012-511A CZ306686B6 (cs) 2012-07-26 2012-07-26 Využití alaptidu jako modifikátoru transdermální penetrace ve farmaceutických kompozicích pro humánní a veterinární aplikace obsahujících antimikrobiální sloučeniny

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