EP1858556A1 - Vehicule pour administration topique de composes anti-inflammatoires - Google Patents

Vehicule pour administration topique de composes anti-inflammatoires

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Publication number
EP1858556A1
EP1858556A1 EP05714631A EP05714631A EP1858556A1 EP 1858556 A1 EP1858556 A1 EP 1858556A1 EP 05714631 A EP05714631 A EP 05714631A EP 05714631 A EP05714631 A EP 05714631A EP 1858556 A1 EP1858556 A1 EP 1858556A1
Authority
EP
European Patent Office
Prior art keywords
set forth
composition
pharmaceutically active
vehicle
active component
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05714631A
Other languages
German (de)
English (en)
Inventor
Joseph Alpharx Inc. SCHWARZ
Michael Alpharx Inc. WEISSPAPIR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alpharx Inc
Original Assignee
Alpharx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alpharx Inc filed Critical Alpharx Inc
Publication of EP1858556A1 publication Critical patent/EP1858556A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the preparation of semisolid formulations for topical delivery of pharmaceutically active ingredients, designed for pain control and inflammation treatment.
  • Topical pharmaceutical preparations of different types have been used for treatment of rheumatic and arthritic pain for decades.
  • Semisolid compositions comprise plant derivatives, such as capsaicin (red hot pepper stinging substance) or turpentine (pine tar component) ointments, homeopathic extract and liniments (Opodeldoc Rus) , mustard plasters, menthol rubs, essential oil balms and many others were used for a long time, mainly as local irritants. Such irritation improves local blood flow, accelerates injured tissue recovery, and switches attention from chronic pain from inflammation.
  • NSAIDs into ointment or cream application onto the desired location allows for effective control of muscle and joint pain intensity. Moreover, when NSAIDs are applied topically, local drug concentration in muscle and joint tissues is significantly higher than in non-treated sites. Additionally, there is no intensive metabolism in liver (so called "first-pass effect”) because such drugs do not pass through the liver before action.
  • NSAIDs The required amount of NSAIDs is lower than an oral dose to achieve similar anti-inflammative and analgesic effects.
  • the most common side effect of NSAIDs is serious irritation of stomach and gastro-intestinal mucosa. This is substantially diminished with local topical applications.
  • Topical NSAID formulations are very popular in Europe, Asia and Far East regions.
  • Examples of such compositions include Voltaren Emulgel® (VoltarolTM in UK), a 1.16% Diclofenac diethylammonium emulsion cream with isopropyl alcohol, Feldene® Gel (0.5% Piroxicam water-ethyl alcohol gel) , Ibuprofen and Ketoprofen gels of different strengths
  • DMSO-containing creams and many other formulations are widespread in many countries as OTC (over the counter) remedies for muscle pain, minor sport injuries, rheumatic and back pain treatment, etc.
  • topical NSAID preparations do not have attributable side-effects such as gastric irritation and internal bleeding.
  • the compounds provide relatively fast action onset and moderate efficacy in treatment of local muscle and joint pain.
  • the main problems of these products is low drug loading due to low solubility in the cream components.
  • High loading can be reached by use of concentrated alcohols, i.e. ethyl alcohol, isopropyl alcohol with polyethylene glycol and propylene glycol suitable as solvents for NSAIDs.
  • Drug loading is high and can easily reach 5-10% or greater, e.g., 5% Ibuprofen gel with isopropyl alcohol, 1% Indomethacin gel based on ethyl alcohol or even 10% Indomethacin ointment with dimethylsulfoxide .
  • NSAIDs Use of more polar hydrophobic compounds may help to improve solubility of NSAIDs.
  • a further method to increase drug solubility in the oil phase is to use highly polar compounds, miscible with the oil phase.
  • Solvents such as Ethoxyethylene glycol (TranscutolTM) , dimethylisosorbide (DMIS) ,
  • Eutectic mixture use in topical applications is rather limited.
  • An example is EMLA cream, developed by Astra- Zeneca.
  • the liquid, formed by mixing two crystalline bases of local anesthetics, Lidocain and Prilocain due to eutectic formation serves as an oil phase in the cream for topical application.
  • the cream, containing 5% of the oil phase, provides excellent stability and anesthetic action.
  • a eutectic mixture of camphor, menthol, thymol and similar compounds is a powerful solvent for non-steroidal anti-inflammatory drugs and other substances.
  • the solubility of Indomethacin, Diclofenac, or Ketoprofen in the mixture increased between 3 and 20 fold.
  • the eutectic mixture was found to be safe, non-toxic and present synergistic behavior in the anti-inflammatory action of NSAIDs due to the antiinflammatory properties of camphor and skin penetration enhancing properties of menthol.
  • the eutectic mixture can be combined with pharmaceutically acceptable oils and lipids and included into topical formulations.
  • the compositions were found to allow much higher drug loading than existing ointment bases and creams, showed no skin irritation and provided enhanced delivery properties for incorporated drugs.
  • menthol Prior to embracing on a discussion of the preparation, some general properties of menthol and camphor will be established.
  • the menthol used was (IR, 2S, 5R) -5-methyl-2- (1- methyethyl) -cyclohexanol with a molecular weight of 156.27 and melting point of 42 0 C.
  • Menthol generally has a peppermint odor. It is well known as a skin irritant and penetration enhancer, as discussed in Tsuk (united States Patent No. 4,933,184). It is widely used in many topical formulations for relief of arthritic and rheumatic pain. Natural L-menthol exerts a cooling or refreshing sensation due to direct interaction with cold sensitive receptors in the skin.
  • camphor 1,7,7- trimethylbicyclo [2, 2, 1] heptanone-2 having a molecular weight of 152.24.
  • Camphor has a high melting point (18O 0 C) and is a very volatile substance with strong pine-like odor that sublimes- even at room temperature and pressure. Initially, camphor found use • as a stimulant, but now camphor is mainly used as a component in topical preparations. It is often used in nasal decongestants and aromatic compositions.
  • Either menthol or camphor separately or in combination are widely used in topical formulations, mainly due to their irritant action, receptor interaction and specific traditional odor, frequently associated with time-honored remedies.
  • Ben GayTM ointment, TigerTM balm, Menthol Chest Rub and similar compositions are well known and popular.
  • Topical preparations for joint relief include that provided for in Lang et al. (United States Patent No. 4,731,200) for an aqueous-alcohol composition containing benzylidene-camphor derivatives, Ivy et al. (United States Patent No. 5,013,726) for a lotion containing methyl salicylate, camphor and menthol, Ivy et al. (United States Patent No. 5,124,320) for an analgesic lotion containing menthol and camphor, Heywang et al . (United States Patent No. 5,144,081) for a pharmaceutical composition containing camphor and Singh (United States Patent No. 5,175,152) for a composition with methyl salicylate, menthol and camphor.
  • the formed mixture is not liquid, but the composition demonstrated a significant improvement in transdermal penetration of testosterone.
  • menthol affects skin permeation by a dual mechanism: by forming a eutectic with the penetrating compound, thereby increasing its solubility in skin ceramides and by altering the barrier properties of the stratum corneum.
  • One aspect of one embodiment of the present invention is thus to provide a vehicle for topical delivery of a pharmaceutically active component, comprising a liquid eutectic mixture containing a hydrophobic component.
  • a further aspect of one embodiment of the . present invention is to provide a composition for topical delivery comprising an oil-in-water or water-in-oil emulsion or microemulsion, wherein the oil phase of the emulsion comprises a vehicle as set forth in claim 3.
  • a method for increasing the solubility of a pharmaceutically active component in a vehicle for topical delivery of the pharmaceutically active component comprising providing a pharmaceutically active component; providing at least two compounds selected from the- group consisting of camphor, menthol, thymol, resorcinol, phenol ' or substituted phenol derivatives; and forming a eutectic mixture containing the pharmaceutically active component and at least two members whereby the mixture contains a greater amount of solubilzed active component relative to a non eutectic mixture.
  • Figure 1 is a graphical representation of Diclofenac (free acid) solubility in a mixture of MCT and a menthol/camphor mixture;
  • Figure 2 is a graphical representation of Indomethacin solubility in oleaginous vehicles and in a menthol/camphor vehicle;
  • Figure 3 is a graphical representation of Piroxicam solubility in oleaginous vehicles and in a eutectic vehicle
  • Figure 4 is a graphical representation of drug content change during storage
  • Figure 5 is a graphical representation of comparative anti-inflammatory activity of topical formulations.
  • Figure 1 graphically represents the solubility of Diclofenac (as free acid) in mixtures of medium chain triglycerides (MCT, standard oil vehicle, Labrafac® TGCC) with different levels of added menthol-camphor eutectic mixture.
  • MCT medium chain triglycerides
  • menthol-camphor eutectic mixture Diclofenac saturation concentration at 25°C was evaluated by HPLC. Solubility in a pure equimolar menthol- camphor eutectic mixture was found to be 11.8 times higher than in pure MCT. Similar behavior was observed also for Indomethacin, illustrated graphically in Figure 2.
  • Piroxicam solubility is significantly lower than aromatic NSAIDs, however, use of the eutectic menthol- camphor mixture increased drug solubility at room temperature between 8 and 11 times, from 0.35 mg/ml in MCT to 2.9-3.2 mg/ml in pure eutectic mixture and to 1.8 mg/ml in MCT with 60% menthol-camphor (1:1) content.
  • alpha-tocopherol or tocopherol acetate is used as the oil phase, solubility can reach 30-35 mg/ml for a tocopherol-menthol-camphor composition 5:3:3 (parts by weight) .
  • Oil phase preparation Soy lecithin, MCT oil and TPGS were mixed together at 45 0 C until a homogenous solution was obtained. TweenTM-80 as then added, followed by the addition of the eutectic mixture vehicle. The mixture was stirred until completely dissolved. Indomethacin (USP grade) was added to the warm mixture and stirred for 10 minutes at 45 0 C until completely dissolved.
  • EDTA disodium salt, glycerin and TweenTM-80 were added to water (90% of calculated amount) and stirred until completely dissolved.
  • the solution was combined with the oil phase, mixed thoroughly using appropriate mixer and homogenized using high pressure homogenizer (Avestin® C-5) at 8,000-12,0009 psi, (600-800 bar). The mixture was passed through the homogenizer between 2 and 3 times.
  • high pressure homogenizer Avestin® C-5
  • the mixture was passed through the homogenizer between 2 and 3 times.
  • Cream preparation
  • Carbopol® 971 P was mixed with 10% of calculated amount of water and soaked for between 2 and ⁇ hours.
  • Carbopol® paste was combined with the homogenized emulsion using a high shear rotor-stator type mixer (Omni GLH mixer) at 18,000-24,000 rpm.
  • Triethanolamine was added gradually while mixing until the desired pH and viscosity were achieved.
  • Bronopol® (2-Brom-2-nitro-l, 3-propanediol) was added to the water phase as an antibacterial preservative.
  • UltrezTM was used as a viscosity regulating component instead of Carbopol® without the preliminary hydration step as set forth in Example 1.
  • composition of the emulsion for 1% Diclofenac cream presented in Table 3.
  • the cream contains approximately 14% of the oil phase with a ratio MCT: Camphor: Menthol of 6:3:4.
  • the oil phase was prepared by dissolving MCT, oil Tocopherol succinate, lecithin, camphor, and menthol at 45°C.
  • the water phase was prepared by dissolving Diclofenac sodium and TweenTM-80 in hot 85°C purified water.
  • Diclofenac sodium emulsion (Example 3A, high loading) was prepared by a similar manner. The composition is identical to that tabulated in Table 3. Balance was adjusted with water and hydrochloric acid.
  • Example 4 Ibuprofen 5% cream
  • Ibuprofen cream was prepared as described in The composition of the emulsion for 5% Diclofenac cream is presented in Table 4. The cream contains approximately 26% of the oil phase with a ratio MCT: Camphor: Menthol of approximately 4.25:1:1.
  • composition was prepared by the method described in Example 4, but L- (-) -menthol was replaced with thymol (2-isopropyl-5-methylphenol) .
  • the cream contained approximately 28% of the oil phase with a ratio MCT: Camphor: • Thymol: Tocopherol acetate of approximately 2:5:5:2.
  • Emulsion with Indomethacin prepared according to U.S. Patent No. 6,113,921.
  • Indomethacin (0.5 g for low loading and 1.0 g for high loading emulsions) was dissolved in a preheated (6O 0 C) mixture of egg lecithin, tocopherol succinate and MCT oil. This mixture was emulsified with a water phase (water with Emulfor EL-620, EDTA sodium and glycerin) using a high shear mixer for 5 minutes at 20,000 rpm to form an emulsion.
  • a water phase water with Emulfor EL-620, EDTA sodium and glycerin
  • Part of emulsion was gelled using Carbopol® 940 to form a cream/ another part was stored at room temperature in tightly closed amber glass containers for 6 months to observe the physical stability.
  • Example 7 Diclofenac sodium 1.0% and 1.5% creams
  • Diclofenac sodium (1.0% and 1.5% drug loading) emulsions were prepared as described in Example 3 and 3A.
  • Example 6 low and high loaded or invention related (Examples 1 and 2) were filtered through PTFE membrane filters .
  • the Indomethacin content in the filtrates was measured using the HPLC method.
  • Figure 4 illustrates the results.
  • the eutectic mixture vehicle emulsion, prepared in accordance with the present invention maintained drug content . Similar results have been obtained for Diclofenac sodium emulsions. In a composition containing 1% of the drug, stability for both formulations was observed. In a composition containing 1.5% Diclofenac sodium emulsion in the menthol-camphor eutectic mixture, stability was observed for at least 3 months at room temperature, while the identically loaded reference emulsion demonstrated significant drug precipitation during the same period.
  • Cream containing salicylic acid was prepared using a different set of surfactants. Salicylic acid was dissolved in the oil phase of the composition, with triethanolamine added to the water phase. After emulsification viscosity was adjusted using Crotix® (Croda) since Carbopol® was found inappropriate as a thickener. Anti inflammatory activity "in vivo":
  • AUC Area Under the Curve
  • the area under the curve reflects the duration and intensity of carrageenan induced inflammation (units are hr*mcl) ; the graeter the edema volume, the higher the inflammation and vice versa.
  • a decrease of AUC corresponds to a decrease of inflammation.
  • AUC for the contol (non- treated) group was assigned to 100%.
  • Indomethacin in the eutectic-based formulation is almost 3 times more active than the same dose of Indomethacin in a conventional cream. Salycilate trolamine in the proposed vehicle demonstrates 50% higher antiinflammatory activity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un véhicule pour l’administration topique d’un principe pharmaceutique actif tel des anti-inflammatoires comprenant un mélange eutectique liquide contenantun composant hydrophobe. Le mélange eutectique contient, par exemple, des composés choisis parmi le camphre, le menthol, le thymol, la résorcine, le phénol ou des dérivés substitués de phénol. L’invention concerne également un procédé d’amélioration de la solubilité dudit principe pharmaceutique actif.
EP05714631A 2005-03-16 2005-03-16 Vehicule pour administration topique de composes anti-inflammatoires Withdrawn EP1858556A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CA2005/000393 WO2006096955A1 (fr) 2005-03-16 2005-03-16 Vehicule pour administration topique de composes anti-inflammatoires

Publications (1)

Publication Number Publication Date
EP1858556A1 true EP1858556A1 (fr) 2007-11-28

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WO (1) WO2006096955A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA018416B1 (ru) 2007-12-06 2013-07-30 Унилевер Н.В. Композиция для ухода за волосами и/или волосистой частью головы
WO2009071422A1 (fr) * 2007-12-06 2009-06-11 Unilever Plc Composition de soin personnel
BR112012012789A2 (pt) * 2009-11-27 2016-08-16 Nuvo Res Inc formulações de ibuprofeno tópicas
CA2785643A1 (fr) 2009-12-23 2011-06-30 Nuvo Research Inc. Formule de terbinafine hautement permeable
JP6121796B2 (ja) * 2012-05-23 2017-04-26 キユーピー株式会社 脂肪乳剤および医薬品組成物中の非ステロイド性抗炎症薬の含有量を高める方法
US9023399B2 (en) 2012-11-16 2015-05-05 NU Technology, LLC Water-soluble anti-inflammatory cream with natural ingredients base
US8613961B1 (en) * 2013-01-09 2013-12-24 NU Technology, LLC Dermatological cream with natural ingredients base
US20140275261A1 (en) * 2013-03-15 2014-09-18 Dr. Reddy's Laboratories, Inc. Diclofenac parenteral compositions
DE102013020633A1 (de) * 2013-12-16 2015-06-18 Epinamics Gmbh Dermale und/oder transdermale pharmazeutische Zusammensetzung enthaltend eine terpenoide Verbindung
WO2016069952A1 (fr) * 2014-10-31 2016-05-06 Sreedhar Rao Rayudu Composition anti-acné et méthodes d'utilisation
WO2020188547A1 (fr) * 2019-03-21 2020-09-24 Universidade Nova De Lisboa Système eutectique profond thérapeutique à base de terpène, son procédé d'obtention et ses utilisations
EP4112042A1 (fr) * 2021-06-30 2023-01-04 GSK Consumer Healthcare SARL Nanoémulsion comprenant du diclofénac

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US7138394B2 (en) * 2002-09-27 2006-11-21 Alpharx Inc. Vehicle for topical delivery of anti-inflammatory compounds

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Title
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