WO2011073998A1 - Composition of dexibuprofen transdermal hydrogel - Google Patents

Composition of dexibuprofen transdermal hydrogel Download PDF

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Publication number
WO2011073998A1
WO2011073998A1 PCT/IN2010/000795 IN2010000795W WO2011073998A1 WO 2011073998 A1 WO2011073998 A1 WO 2011073998A1 IN 2010000795 W IN2010000795 W IN 2010000795W WO 2011073998 A1 WO2011073998 A1 WO 2011073998A1
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WO
WIPO (PCT)
Prior art keywords
dexibuprofen
alcoholic
hydrogel
transdermal hydrogel
sodium
Prior art date
Application number
PCT/IN2010/000795
Other languages
French (fr)
Inventor
Jeffrey Stuart Bergman
Sampathkumar Devarajan
Selvakumar Ramalingam
Anandsenthil Vel Palanisamy
Original Assignee
Shasun Pharmaceuticals Limited
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
Priority to JP2012543996A priority Critical patent/JP2013514347A/en
Priority to CN2010800577381A priority patent/CN102665681A/en
Priority to BR112012014558A priority patent/BR112012014558B8/en
Priority to CA2784827A priority patent/CA2784827C/en
Application filed by Shasun Pharmaceuticals Limited filed Critical Shasun Pharmaceuticals Limited
Priority to KR1020127017992A priority patent/KR101884951B1/en
Priority to DK10837172.5T priority patent/DK2512446T3/en
Priority to EP10837172.5A priority patent/EP2512446B1/en
Priority to ES10837172.5T priority patent/ES2541483T3/en
Priority to RU2012129527/15A priority patent/RU2012129527A/en
Priority to AU2010331761A priority patent/AU2010331761B2/en
Priority to PL10837172T priority patent/PL2512446T3/en
Priority to MX2012007062A priority patent/MX352187B/en
Publication of WO2011073998A1 publication Critical patent/WO2011073998A1/en
Priority to US13/525,432 priority patent/US20120259018A1/en
Priority to US14/824,787 priority patent/US10085939B2/en

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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
    • A61K9/06—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
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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]
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a topical pharmaceutical composition containing dexibuprofen [(S)-2-(4-isobutylphenyl) propionic acid] and the process for preparing the same.
  • Ibuprofen (2-(4-isobutylphenyl) propionic acid) has one chiral center, thus there are two enantiomers, S (+)-ibuprofen (dexibuprofen) and R (-)-ibuprofen, also known as (S+)- ibuprofen and (R-)-ibuprofen.
  • S (+)-ibuprofen (dexibuprofen) and R (-)-ibuprofen
  • S+)- ibuprofen also known as (S+)- ibuprofen and (R-)-ibuprofen.
  • the racemic form consisting of equal amounts of S(+)- ibuprofen and R(-)-ibuprofen is exclusively used in the currently available commercial preparations, as well as the water soluble salts of ibuprofen such as lysinate, arginate, sodium, potassium etc are also used.
  • Racemic ibuprofen has relatively high melting point (about 78° C), while both stereoisomer' s of ibuprofen, S (+)-ibuprofen and R (-)-ibuprofen, melt at 52°C to 54°C. All the different forms of ibuprofen are poorly soluble in water Notably, the S (+) form alone appears to be responsible for the anti-inflammatory activity, not the R (-) form (S. Adams et al., Curr. Med. Res. Opin,. 3, 552 (1975); S. Adams et al., J. Pharm. Pharmaco., 28, 256-257 (1976)).
  • US Patent no 5093133 discloses hydroalcoholic gel formulations of (S)-ibuprofen as an effective vehicle for percutaneous delivery of (S+)-ibuprofen through the skin.
  • the hydroalcoholic gel of (S+)-ibuprofen is prepared by using 40 to 60% of alcohol; 0-20% of a non-volatile solvent; 2.0 to 5.0% of gelling agents; sufficient base, to adjust the pH to between 3.5 to 6.0; and water.
  • US Patent no 5767161 discloses a pharmaceutical composition in the form of cream, foam or stick containing 2.5-10% by weight (S)-2-(4-isobutylphenyl)propionic acid, 20-30% by weight ethanol and 5-50% by weight propylene glycol, the ratio of ethanol to propylene glycol is 0.6-1 to 4:1.
  • This patent also reports an increase in cutaneous permeation of the active ingredient with respect to those obtained by known topical pharmaceutical compositions containing an equivalent or higher amount of Ibuprofen.
  • US Patent no 6368618 discloses a novel two phase liquid topical formulation for delivery of S(+)-ibuprofen, which is characterized by enhanced transdermal absorption and efficacy.
  • the oil phase contains a relatively high concentration of the S (+)-ibuprofen making it directly available for partitioning into the stratum comeum without the rate-limiting diffusion process from the inert oil phase as in a conventional cream.
  • US Patent no 5696165 discloses pharmaceutical compositions for oral, rectal or topical administration containing (S)-Ibuprofen sodium salt as an active ingredient.
  • This patent reports that the S(-)sodium 2-(4-isobutylphenyl) propionate has advantage over S(+) 2-(4- isobutylphenyl)propionate for preparing pharmaceutical compositions containing water and additional formulation advantage is that S(-)sodium 2-(4-isobutylphenyl)propionate will resist esterification with excipients which contain a hydroxyl group for example mono-, di-, tri- or polyhydric alcohols.
  • dexibuprofen is formulated into topical formulations either using high amount of alcohol or using a two phase system to enhance the transdermal absorption and efficacy.
  • One of the objective(s) of the present invention is to prepare a non-alcoholic transdermal hydrogel of dexibuprofen.
  • Another objective of the present invention is to prepare a clear transparent non-alcoholic transdermal hydrogel of dexibuprofen.
  • the present invention relates to a pharmaceutical composition for topical use containing dexibuprofen, more particularly to a non-alcoholic dexibuprofen transdermal hydrogel and process of preparing the same.
  • Stable non-alcoholic transdermal hydrogel of dexibuprofen was prepared by using a simple manufacturing process, and the experimental trials showed that the pH modifying agent, antioxidant and water miscible solvent are the essential excipients to obtain stable non-alcoholic transdermal hydrogel of dexibuprofen.
  • the dexibuprofen hydrogel prepared using carbopol as a gelling polymer produced an opaque gel
  • hydrogel prepared using hyroxypropyl methylcellulose (HPMC) as a gelling polymer produced a transparent gel.
  • HPMC hyroxypropyl methylcellulose
  • the present invention relates to a pharmaceutical composition for topical use containing dexibuprofen, more particularly to a non-alcoholic transdermal hydrogel of dexibuprofen and process of preparing the same.
  • Topical NSAIDs preparations are commonly use to treat pain and inflammation associated with joints and muscles. Topical NSAIDs have three major advantages over oral treatment of pain and inflammation associated with joints and muscles: i) higher concentrations of NSAIDs are delivered to the desire site; ii) only 1-3% of NSAIDs is systemically absorbed, reducing the possibility of gastrointestinal upset or ulcers; and iii) low blood levels reduce the incidence of drug interactions.
  • Ibuprofen topical preparations are available for the treatment of pain and inflammation associated with joints and muscles.
  • Ibuprofen (2-(4-isobutylphenyl) propionic acid) has one chiral center, thus there are two enantiomers, S (+)-ibuprofen (dexibuprofen) and R (-)- ibuprofen, also known as (S)-ibuprofen and (R)-ibuprofen.
  • S(+) form alone appears to be responsible for the anti-inflammatory activity, not the R(-) form (S. Adams et al., Curr. Med. Res. Opin. 3, 552 (1975); S. Adams et al., J. Pharm. Pharmaco., 28, 256-257 (1976)).
  • the popular topical NSATDs preparations include cream, ointment and gel, now a day's topical hydrogels are gaining popularity because of their cooling 'effect, and non-greasy nature.
  • dexibuprofen is formulated into topical gel formulations either using high amount of alcohol or using a two phase system to enhance the transdermal absorption and efficacy.
  • the present invention relates to a pharmaceutical composition for topical use containing dexibuprofen more particularly to non-alcoholic transdermal hydrogel of dexibuprofen and process of preparing the same.
  • process of preparing a non-alcoholic transdermal hydrogel of dexibuprofen comprising the steps of: step (i) disperse the gelling polymer(s) in purified water and allow it to soak overnight, step (ii) dissolve the preservative(s) in purified water and then disperse dexibuprofen in it, step (iii) dissolve the menthol in triemanolamine, step (iv) mix step (iii) with step (ii) with continuous stirring, step (v) mix propylene glycol and PEG 400; add this mixture to transcutol-P followed by the addition of lavender oil and mix well, step (vi) add step (v) to step (iv) and mix well, and
  • step (vii) finally add step (vi) to step (i) with constant stirring to obtain homogenous gel.
  • non-alcoholic transdermal hydrogel of dexibuprofen may be transparent or translucent or opaque in nature.
  • the present invention comprises one or more pharmaceutically acceptable excipient(s) selected from the group comprising of gelling agent, pH modifying agent, spreadability modifying agent, water miscible solvent, soothing agent, preservative, antioxidant, surfactant, chelating agent, permeation enhancer, antifoaming agent and flavoring agent etc.
  • one or more gelling agent(s) can be selected from the group comprising of carbomer, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), poloxamer, hydroxypropyl cellulose (HPC), methylcellulose (MC), collagen, gelatin, agar, alginic acid and its sodium salts such as sodium alginate, carrageenans and its sodium or potassium salts, tragacanth, pectin, guar gum, xanthan gum, gellan gum, polyacrylamide, polyvinyl alcohol, polyethylene and its co-polymers and the like.
  • HPMC hydroxypropyl methylcellulose
  • HEC hydroxyethyl cellulose
  • HPC hydroxypropyl cellulose
  • MC methylcellulose
  • collagen gelatin
  • agar alginic acid and its sodium salts such as sodium alginate, carrageenans and its sodium or potassium salts
  • tragacanth pectin
  • guar gum x
  • one or more pH modifying agent(s) can be selected from the group comprising of sodium hydroxide, citric acid, sodium citrate, triethanolamine, diemanolamine and the like.
  • one or more soothing agent(s) can be selected from the group comprising of menthol, thymol, camphor and the like.
  • one or more preservative(s) can be selected from the group comprising of sodium salts of methyl paraben, propyl paraben, other preservatives like salicylic acid and its salts, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate and the like.
  • At least one oil-soluble and/or water soluble antioxidant(s) can be selected from the group comprising of butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxanisole (BHA), phenyl-a-naphthylamine, hydroquinone, propyl gallate, nordihydroguiaretic acid, ascorbic acid, sodium benzoate, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid, thioglyerol, thiosorbitol, thiourea, thioglycolic acid, cysteine hydrochloride, 1,4- diazobicyclo-(2,2,2)-octane and the like,
  • one or more surfactant(s) can be selected from the group comprising of sodium alkyl sulfates such as sodium lauryl
  • one or more water miscible solvent can be selected from the group comprising of polyethylene glycol, propylene glycol, glycerin and the like.
  • the water miscible solvent i.e. a cosolvent
  • one or more permeation enhancer(s) can be selected from the group comprising of caprylic acid and its derivatives, polyoxylglycerides and its derivatives, triglycerides and its derivatives, lauric acid and its derivatives, oleic acid and its derivatives, diethylene glycol monoethyl ether (Transcutol-P), and the like.
  • one or more chelating agent(s) can be selected from the group comprising of emylenediaminetetraacetic acid (EDTA), sodium EDTA, disodium EDTA, citric acid, tartaric acid and the like.
  • one or more antifoaming agents can be selected from the group comprising of simethicone, dimethicone and the like.
  • one or more flavoring agent(s) can be selected from the group comprising of lavender oil, rose oil, menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, wintergreen oil, clove oil, eucalyptus oil and the like.
  • Example- 1 (Table- 1) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using carbopol as gelling polymer:
  • step 3 Dissolve menthol in triethanolamine. 4. Add step 3 to step 2 with constant stirring to get clear solution.
  • step 5 Add step 5 to step 4 and mix well.
  • step 6 Finally add step 6 to step 1 with constant stirring to obtain homogenous gel.
  • Example-2 (Table-2) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using HPMC as gelling polymer:
  • step 4 Add step 4 to step 3 with constant stirring to get clear solution.
  • step 6 Add step 6 to step 5.
  • Step 7 Add Step 7 to step 2 with constant stirring to obtain a homogenous gel.
  • Example-3 (Table-3) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using carbopol as gelling polymer
  • step 3 Add step 3 to step 2 with constant stirring to get clear solution.
  • step 5 Add step 5 to step 4 and mix well.
  • Example-4 (Table-4) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using HPMC as gelling polymer
  • step 4 Add step 4 to step 3 with constant stirring to get clear solution.
  • step 6 Add step 6 to step 5.
  • Step 7 Add Step 7 to step 2 with constant stirring to obtain a homogenous gel.
  • the experimental trials showed that the pH modifying agent, antioxidant and water miscible solvent are essential excipients for obtaining stable non-alcoholic transdermal hydrogel of dexibuprofen.
  • the hydrogels prepared according to example 1 and 3 using carbopol as gelling polymer produced opaque gel, whereas hydrogels prepared according to example 2 and 4 using HPMC as gelling polymer produced transparent gel. Further the hydrogels prepared according to example 1, 2, 3 and 4 were subjected for stability study at 40°C / 75% RH for 3 months in laminated tubes and there was no significant change with respect to physical description, pH, assay value and related substances.
  • Table 5 Stability data of dexibuprofen non-alcoholic transdermal hydrogels prepared according to example 1, 2, 3, and 4 at 40°C / 75% RH is as follows.

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Abstract

Stable non-alcoholic transdermal hydrogel of dexibuprofen was prepared by using a simple manufacturing process, and the experimental trials showed that the pH modifying agent, antioxidant and water miscible solvent are the essential excipients to obtain stable non-alcoholic transdermal hydrogel of dexibuprofen. The dexibuprofen hydrogel prepared using carbopol as a gelling polymer produced an opaque gel, whereas hydrogel prepared using hyroxypropyl methylcellulose (HPMC) as a gelling polymer produced a transparent gel. There was no significant changes observed with respect to physical description, pH, assay and particularly to the related substance values when the hydrogels were subjected to the stability study at accelerated condition (40°C / 75% RH) for 3 months in laminated tubes.

Description

COMPOSITION OF DEXIBUPROFEN TRANSDERMAL HYDROGEL
NOVEL COMPOSITION OF DEXIBUPROFEN TRANSDERMAL HYDROGEL
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a topical pharmaceutical composition containing dexibuprofen [(S)-2-(4-isobutylphenyl) propionic acid] and the process for preparing the same.
BACKGROUND OF THE INVENTION:
Ibuprofen (2-(4-isobutylphenyl) propionic acid) has one chiral center, thus there are two enantiomers, S (+)-ibuprofen (dexibuprofen) and R (-)-ibuprofen, also known as (S+)- ibuprofen and (R-)-ibuprofen. The racemic form consisting of equal amounts of S(+)- ibuprofen and R(-)-ibuprofen is exclusively used in the currently available commercial preparations, as well as the water soluble salts of ibuprofen such as lysinate, arginate, sodium, potassium etc are also used. Racemic ibuprofen has relatively high melting point (about 78° C), while both stereoisomer' s of ibuprofen, S (+)-ibuprofen and R (-)-ibuprofen, melt at 52°C to 54°C. All the different forms of ibuprofen are poorly soluble in water Notably, the S (+) form alone appears to be responsible for the anti-inflammatory activity, not the R (-) form (S. Adams et al., Curr. Med. Res. Opin,. 3, 552 (1975); S. Adams et al., J. Pharm. Pharmaco., 28, 256-257 (1976)).
US Patent no 5093133 discloses hydroalcoholic gel formulations of (S)-ibuprofen as an effective vehicle for percutaneous delivery of (S+)-ibuprofen through the skin. In this patent, the hydroalcoholic gel of (S+)-ibuprofen is prepared by using 40 to 60% of alcohol; 0-20% of a non-volatile solvent; 2.0 to 5.0% of gelling agents; sufficient base, to adjust the pH to between 3.5 to 6.0; and water.
US Patent no 5767161 discloses a pharmaceutical composition in the form of cream, foam or stick containing 2.5-10% by weight (S)-2-(4-isobutylphenyl)propionic acid, 20-30% by weight ethanol and 5-50% by weight propylene glycol, the ratio of ethanol to propylene glycol is 0.6-1 to 4:1. This patent also reports an increase in cutaneous permeation of the active ingredient with respect to those obtained by known topical pharmaceutical compositions containing an equivalent or higher amount of Ibuprofen. US Patent no 6368618 discloses a novel two phase liquid topical formulation for delivery of S(+)-ibuprofen, which is characterized by enhanced transdermal absorption and efficacy. In this patent two phase system consist of an aqueous and oil phases, the oil phase contains a relatively high concentration of the S (+)-ibuprofen making it directly available for partitioning into the stratum comeum without the rate-limiting diffusion process from the inert oil phase as in a conventional cream.
US Patent no 5696165 discloses pharmaceutical compositions for oral, rectal or topical administration containing (S)-Ibuprofen sodium salt as an active ingredient. This patent reports that the S(-)sodium 2-(4-isobutylphenyl) propionate has advantage over S(+) 2-(4- isobutylphenyl)propionate for preparing pharmaceutical compositions containing water and additional formulation advantage is that S(-)sodium 2-(4-isobutylphenyl)propionate will resist esterification with excipients which contain a hydroxyl group for example mono-, di-, tri- or polyhydric alcohols.
As disclosed in the prior arts dexibuprofen is formulated into topical formulations either using high amount of alcohol or using a two phase system to enhance the transdermal absorption and efficacy.
Thus, there is a constant need to formulate topical formulation of dexibuprofen which can be prepared by simple manufacturing process and should also provide an effective transdermal penetration.
OBJECTIVES OF THE INVENTION One of the objective(s) of the present invention is to prepare a non-alcoholic transdermal hydrogel of dexibuprofen.
Another objective of the present invention is to prepare a clear transparent non-alcoholic transdermal hydrogel of dexibuprofen.
SUMMARY OF THE INVENTION:
The present invention relates to a pharmaceutical composition for topical use containing dexibuprofen, more particularly to a non-alcoholic dexibuprofen transdermal hydrogel and process of preparing the same. Stable non-alcoholic transdermal hydrogel of dexibuprofen was prepared by using a simple manufacturing process, and the experimental trials showed that the pH modifying agent, antioxidant and water miscible solvent are the essential excipients to obtain stable non-alcoholic transdermal hydrogel of dexibuprofen. The dexibuprofen hydrogel prepared using carbopol as a gelling polymer produced an opaque gel, whereas hydrogel prepared using hyroxypropyl methylcellulose (HPMC) as a gelling polymer produced a transparent gel. There was no significant changes observed with respect to physical description, pH, assay and particularly to the related substance values when the hydrogels were subjected to the stability study at accelerated condition (40°C / 75% RH) for 3 months in laminated tubes.
DETAILED DESCRDTION OF THE INVENTION:
The present invention relates to a pharmaceutical composition for topical use containing dexibuprofen, more particularly to a non-alcoholic transdermal hydrogel of dexibuprofen and process of preparing the same.
Topical NSAIDs preparations are commonly use to treat pain and inflammation associated with joints and muscles. Topical NSAIDs have three major advantages over oral treatment of pain and inflammation associated with joints and muscles: i) higher concentrations of NSAIDs are delivered to the desire site; ii) only 1-3% of NSAIDs is systemically absorbed, reducing the possibility of gastrointestinal upset or ulcers; and iii) low blood levels reduce the incidence of drug interactions.
Ibuprofen topical preparations are available for the treatment of pain and inflammation associated with joints and muscles. Ibuprofen (2-(4-isobutylphenyl) propionic acid) has one chiral center, thus there are two enantiomers, S (+)-ibuprofen (dexibuprofen) and R (-)- ibuprofen, also known as (S)-ibuprofen and (R)-ibuprofen. Notably, the S(+) form alone appears to be responsible for the anti-inflammatory activity, not the R(-) form (S. Adams et al., Curr. Med. Res. Opin. 3, 552 (1975); S. Adams et al., J. Pharm. Pharmaco., 28, 256-257 (1976)). The popular topical NSATDs preparations include cream, ointment and gel, now a day's topical hydrogels are gaining popularity because of their cooling 'effect, and non-greasy nature.
In the prior arts, dexibuprofen is formulated into topical gel formulations either using high amount of alcohol or using a two phase system to enhance the transdermal absorption and efficacy.
The present invention relates to a pharmaceutical composition for topical use containing dexibuprofen more particularly to non-alcoholic transdermal hydrogel of dexibuprofen and process of preparing the same.
According to the present invention, process of preparing a non-alcoholic transdermal hydrogel of dexibuprofen comprising the steps of: step (i) disperse the gelling polymer(s) in purified water and allow it to soak overnight, step (ii) dissolve the preservative(s) in purified water and then disperse dexibuprofen in it, step (iii) dissolve the menthol in triemanolamine, step (iv) mix step (iii) with step (ii) with continuous stirring, step (v) mix propylene glycol and PEG 400; add this mixture to transcutol-P followed by the addition of lavender oil and mix well, step (vi) add step (v) to step (iv) and mix well, and
step (vii) finally add step (vi) to step (i) with constant stirring to obtain homogenous gel.
According to the present invention non-alcoholic transdermal hydrogel of dexibuprofen may be transparent or translucent or opaque in nature.
Other than active ingredient dexibuprofen, the present invention comprises one or more pharmaceutically acceptable excipient(s) selected from the group comprising of gelling agent, pH modifying agent, spreadability modifying agent, water miscible solvent, soothing agent, preservative, antioxidant, surfactant, chelating agent, permeation enhancer, antifoaming agent and flavoring agent etc.
According to the present invention one or more gelling agent(s) can be selected from the group comprising of carbomer, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), poloxamer, hydroxypropyl cellulose (HPC), methylcellulose (MC), collagen, gelatin, agar, alginic acid and its sodium salts such as sodium alginate, carrageenans and its sodium or potassium salts, tragacanth, pectin, guar gum, xanthan gum, gellan gum, polyacrylamide, polyvinyl alcohol, polyethylene and its co-polymers and the like.
According to the present invention one or more pH modifying agent(s) can be selected from the group comprising of sodium hydroxide, citric acid, sodium citrate, triethanolamine, diemanolamine and the like.
According to the present invention one or more soothing agent(s) can be selected from the group comprising of menthol, thymol, camphor and the like.
According to the present invention one or more preservative(s) can be selected from the group comprising of sodium salts of methyl paraben, propyl paraben, other preservatives like salicylic acid and its salts, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate and the like.
According to the present invention at least one oil-soluble and/or water soluble antioxidant(s) can be selected from the group comprising of butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxanisole (BHA), phenyl-a-naphthylamine, hydroquinone, propyl gallate, nordihydroguiaretic acid, ascorbic acid, sodium benzoate, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid, thioglyerol, thiosorbitol, thiourea, thioglycolic acid, cysteine hydrochloride, 1,4- diazobicyclo-(2,2,2)-octane and the like, According to the present invention one or more surfactant(s) can be selected from the group comprising of sodium alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates such as sodium N-lauroyl sarcosinate and sodium N- myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate, N-acyl glutamates such as N- palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate, sodium dioctylsulfosuccinate; N-alkylaminoglycerols such as N- laui ldiaminoethylglycerol and N-myristyldiaminoethylglycerol, N-alkyl-N- carboxymethylammomum betaine, sodium 2-alkyl-l-hydroxyemylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerol ester, sorbitan aliphatic acid ester, pluronic type surface active agent, and polyoxyethylenesorbitan aliphatic acid esters such as polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan monolaurate and the like. According to the present invention one or more spreadability modifying agent(s) can be selected from the group comprising of polyethylene glycol, propylene glycol, glycerin, light liquid paraffin and the like.
According to the present invention one or more water miscible solvent (s) can be selected from the group comprising of polyethylene glycol, propylene glycol, glycerin and the like. The water miscible solvent (i.e. a cosolvent) will be present, to assist in dissolving the active agent other essential excipients.
According to the present invention one or more permeation enhancer(s) can be selected from the group comprising of caprylic acid and its derivatives, polyoxylglycerides and its derivatives, triglycerides and its derivatives, lauric acid and its derivatives, oleic acid and its derivatives, diethylene glycol monoethyl ether (Transcutol-P), and the like.
According to the present invention one or more chelating agent(s) can be selected from the group comprising of emylenediaminetetraacetic acid (EDTA), sodium EDTA, disodium EDTA, citric acid, tartaric acid and the like. According to the present invention one or more antifoaming agents can be selected from the group comprising of simethicone, dimethicone and the like.
According to the present invention one or more flavoring agent(s) can be selected from the group comprising of lavender oil, rose oil, menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, wintergreen oil, clove oil, eucalyptus oil and the like.
EXAMPLES:
Following examples are illustrative but no way limits the scope of the invention Example- 1 (Table- 1) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using carbopol as gelling polymer:
Figure imgf000008_0001
Manufacturing procedure of example 1 :
1. Disperse the Carbopol 97 IP in purified water under stirring for 15 minutes and allow it to soak overnight.
2. Dissolve sodium metabisulpbite and sodium benzoate in purified water and then disperse dexibuprofen in it.
3. Dissolve menthol in triethanolamine. 4. Add step 3 to step 2 with constant stirring to get clear solution.
5. Mix propylene glycol and PEG 400, add this mixture to transcutol-P followed by
lavender oil and mix well.
6. Add step 5 to step 4 and mix well.
7. Finally add step 6 to step 1 with constant stirring to obtain homogenous gel.
Example-2 (Table-2) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using HPMC as gelling polymer:
Figure imgf000009_0001
Manufacturing procedure of example 2:
1. Disperse HPMC K4M, HPMC E5, Lutrol F68 in purified water under stirring for 15 minutes, and allow it to soak overnight.
2. Add simethicone to step 1 and mix well.
3. Dissolve sodium metabisulphite and sodium benzoate in water and then disperse
dexibuprofen in it.
4. Dissolve menthol in triethanolamine.
5. Add step 4 to step 3 with constant stirring to get clear solution.
6. Mix propylene glycol, PEG 400 and add this mixture to transcutol-P followed by
lavender oil and mixed well. 7. Add step 6 to step 5.
8. Add Step 7 to step 2 with constant stirring to obtain a homogenous gel.
Example-3 (Table-3) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using carbopol as gelling polymer
Manufacturing procedure of example 3:
1. Disperse the Carbopol 97 IP in purified water under stirring for 15 minutes and allow it to soak overnight.
2. Dissolve sodium metabisulphite and sodium benzoate in purified water and then disperse dexibuprofen in it.
3. Dissolve menthol in triemanolamine.
4. Add step 3 to step 2 with constant stirring to get clear solution.
5. Mix propylene glycol and PEG 400, add this mixture to transcutol-P followed by
lavender oil and mix well.
6. Add step 5 to step 4 and mix well.
7. Finally add step 6 to step 1 with constant stirring to obtain homogenous gel. Example-4 (Table-4) Dexibuprofen non-alcoholic transdermal hydrogel prepared by using HPMC as gelling polymer
Figure imgf000011_0001
Manufacturing Procedure of Example 4:
1. Disperse HPMC K4M, HPMC E5, Lutrol F68 in purified water under stirring for 15 minutes, and allow it to soak overnight.
2. Add simethicone to step 1 and mix well.
3. Dissolve sodium metabisulphite and sodium benzoate in water and then disperse
dexibuprofen in it.
4. Dissolve menthol in triethanolamine.
5. Add step 4 to step 3 with constant stirring to get clear solution.
6. Mix propylene glycol, PEG 400 and add this mixture to transcutol-P followed by
lavender oil and mixed well.
7. Add step 6 to step 5.
8. Add Step 7 to step 2 with constant stirring to obtain a homogenous gel.
The experimental trials showed that the pH modifying agent, antioxidant and water miscible solvent are essential excipients for obtaining stable non-alcoholic transdermal hydrogel of dexibuprofen. The hydrogels prepared according to example 1 and 3 using carbopol as gelling polymer produced opaque gel, whereas hydrogels prepared according to example 2 and 4 using HPMC as gelling polymer produced transparent gel. Further the hydrogels prepared according to example 1, 2, 3 and 4 were subjected for stability study at 40°C / 75% RH for 3 months in laminated tubes and there was no significant change with respect to physical description, pH, assay value and related substances.
Table 5: Stability data of dexibuprofen non-alcoholic transdermal hydrogels prepared according to example 1, 2, 3, and 4 at 40°C / 75% RH is as follows.
Figure imgf000012_0001

Claims

WE CLAIM:
1. A non-alcoholic transdermal hydrogel of dexibuprofen.
2. A non-alcoholic transparent transdermal hydrogel of dexibuprofen.
3. A non-alcoholic transdermal hydrogel of dexibuprofen essentially comprising of one or more pH modifying agent, antioxidant and water miscible solvent.
4. A non-alcoholic transdermal hydrogel of dexibuprofen according to any of the preceding claims further comprise of one or more of surfactant, antifoaming agent, chelating agent, gelling polymer, preservative, permeation enhancer, soothing agent, and flavoring agent.
5. A non-alcoholic transdermal hydrogel of dexibuprofen according to claim 4, wherein one or more gelling agent may be selected from the group comprising of carbomer, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose (MC), poloxamer, sodium alginate, carrageenans, tragacanth, pectin, guar gum, xanthan gum, gellan gum and polyacrylamid.
6. A non-alcoholic transdermal hydrogel of dexibuprofen according to claim 3, wherein one or more water miscible solvent may be selected from the group comprising of polyethylene glycol, propylene glycol, and glycerin.
7. A non-alcoholic transdermal hydrogel of dexibuprofen according to claim 3, wherein one or more pH modifying agent may be selected from the group comprising of sodium hydroxide, citric acid, sodium citrate, triethanolamine, and diethanolamine.
8. A non-alcoholic transdermal hydrogel of dexibuprofen according to claim 3, wherein one or more antioxidant may be selected from the group comprising of sodium benzoate, sodium metabisulfite, butylated hydroxytoluene (BHT), and butylated hydroxanisole (BHA).
9. A non-alcoholic transdermal hydrogel of dexibuprofen according to any of the preceding claims may be transparent or translucent or opaque in nature.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016510036A (en) * 2013-02-28 2016-04-04 ノヴァン，インコーポレイテッド Topical composition and method of using the same
US10206947B2 (en) 2013-08-08 2019-02-19 Novan, Inc. Topical compositions and methods of using the same
US10226483B2 (en) 2013-08-08 2019-03-12 Novan, Inc. Topical compositions and methods of using the same
US10322081B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
US10322082B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
US10912743B2 (en) 2016-03-02 2021-02-09 Novan, Inc. Compositions for treating inflammation and methods of treating the same
US11166980B2 (en) 2016-04-13 2021-11-09 Novan, Inc. Compositions, systems, kits, and methods for treating an infection
EP3713549B1 (en) * 2017-11-21 2024-06-19 LTS Lohmann Therapie-Systeme AG Transdermal therpeutic syste based on adhesive plasticizer-polymer-matrices
US12054766B2 (en) 2014-08-20 2024-08-06 Neogen Food Safety Us Holdco Corporation Devices and methods for sample partitioning and analysis

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101894891B1 (en) * 2012-11-30 2018-09-04 동아에스티주식회사 Topical gel composition containing dexibuprofen emulsion with enhaced permeability
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EP4308088A4 (en) 2021-11-08 2024-06-12 Weiyong Li Transdermal drug delivery system for delivering a drug to a patient
KR102419076B1 (en) * 2022-01-17 2022-07-08 장보경 Anesthetic composition and method for preparing same

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767751A (en) * 1984-01-25 1988-08-30 Beecham Group P.L.C. Topical drug release system
WO1995011017A1 (en) 1993-10-20 1995-04-27 The Boots Company Plc Ibuprofen and flurbiprofen as anti-pruritic agents
US5894019A (en) 1995-03-17 1999-04-13 Gebro Broschek Gesellschaft M.B.H. Topically applied pharmaceutical composition, method of preparing it and its use
DE19945522A1 (en) 1999-09-23 2001-04-05 Hexal Ag Pharmaceutical gel containing active ingredients
US20040202722A1 (en) * 2003-04-11 2004-10-14 Robert Fishman Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof
US20070020325A1 (en) * 2005-07-22 2007-01-25 Hisamitsu Pharmaceutical Co., Inc. Hydrogel composition

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684666A (en) * 1986-08-19 1987-08-04 Haas Pharmaceuticals, Inc. Stabilized liquid analgesic compositions
DE4024801A1 (en) * 1990-08-04 1992-02-06 Porsche Ag EXHAUST SYSTEM OF AN INTERNAL COMBUSTION ENGINE
RO118371B1 (en) * 1991-05-13 2003-05-30 Boots Co Plc Pharmaceutical composition containing a sodium salt of s(-)ibuprofen
WO1996040849A1 (en) * 1995-06-07 1996-12-19 Lee County Mosquito Control District Lubricant compositions and methods
US20010023261A1 (en) * 1997-01-27 2001-09-20 Lg Chemical Limited. Novel composition for the transdermal administration of drugs
AU3212199A (en) * 1998-03-31 1999-10-18 Scimed Life Systems, Inc. Temperature controlled solute delivery system
US6399093B1 (en) * 1999-05-19 2002-06-04 Advanced Medical Instruments Method and composition to treat musculoskeletal disorders
WO2001001962A1 (en) * 1999-07-05 2001-01-11 Idea Ag. A method for the improvement of transport across adaptable semi-permeable barriers
US20020102301A1 (en) * 2000-01-13 2002-08-01 Joseph Schwarz Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof
KR100452972B1 (en) * 2000-05-16 2004-10-14 주식회사 삼양사 Hydrogel composition for transdermal drug
DE60233217D1 (en) * 2001-05-01 2009-09-17 Corium Internat Inc HYDROGEL COMPOSITIONS
US20030082225A1 (en) * 2001-10-19 2003-05-01 Mason Paul Arthur Sterile, breathable patch for treating wound pain
AR041021A1 (en) * 2002-08-22 2005-04-27 Novartis Consumer Health Sa TOPICAL COMPOSITION
EP1633408B1 (en) * 2003-06-19 2016-08-17 Coloplast A/S A wound care device
PE20050288A1 (en) * 2003-07-02 2005-04-29 Alza Corp METHOD AND IMMUNIZATION PATCH BY MICROPROJECTION DISPOSAL
CH715855B1 (en) * 2003-08-28 2020-08-14 Mibelle Ag Preparation consisting of at least two nanoemulsions.
JP4128521B2 (en) * 2003-12-19 2008-07-30 信越化学工業株式会社 Gel sheet and method for producing the same
WO2006122183A2 (en) * 2005-05-10 2006-11-16 Cytophil, Inc. Injectable hydrogels and methods of making and using same
WO2007041526A2 (en) * 2005-09-30 2007-04-12 Transcutaneous Technologies Inc. Iontophoresis apparatus and method to deliver antibiotics to biological interfaces
GB0718435D0 (en) * 2007-09-21 2007-10-31 Northern Health And Social Car Wpund care formulation
CN101455654B (en) * 2007-12-13 2013-03-06 天津医科大学 Arginine ibuprofen gel and preparation method thereof
US8383614B2 (en) * 2008-01-31 2013-02-26 The Trustees Of The University Of Pennsylvania Hypercholestrolemia and tendinous injuries
BRPI0918142A2 (en) * 2008-09-10 2015-12-01 Biochemics Inc topical pharmacological composition, its method of preparation, as well as use of the 2- (4-isobutyphylphenyl) propionic acid free form

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767751A (en) * 1984-01-25 1988-08-30 Beecham Group P.L.C. Topical drug release system
WO1995011017A1 (en) 1993-10-20 1995-04-27 The Boots Company Plc Ibuprofen and flurbiprofen as anti-pruritic agents
US5894019A (en) 1995-03-17 1999-04-13 Gebro Broschek Gesellschaft M.B.H. Topically applied pharmaceutical composition, method of preparing it and its use
DE19945522A1 (en) 1999-09-23 2001-04-05 Hexal Ag Pharmaceutical gel containing active ingredients
US20040202722A1 (en) * 2003-04-11 2004-10-14 Robert Fishman Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof
US20070020325A1 (en) * 2005-07-22 2007-01-25 Hisamitsu Pharmaceutical Co., Inc. Hydrogel composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2512446A4

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021121619A (en) * 2013-02-28 2021-08-26 ノヴァン，インコーポレイテッド Topical compositions and methods of using the same
US10258564B2 (en) 2013-02-28 2019-04-16 Novan, Inc. Topical compositions and methods of using the same
JP2016510036A (en) * 2013-02-28 2016-04-04 ノヴァン，インコーポレイテッド Topical composition and method of using the same
JP7125526B2 (en) 2013-02-28 2022-08-24 ノヴァン，インコーポレイテッド Topical composition and method of using same
US11285098B2 (en) 2013-02-28 2022-03-29 Novan, Inc. Topical compositions and methods of using the same
US10206947B2 (en) 2013-08-08 2019-02-19 Novan, Inc. Topical compositions and methods of using the same
US10226483B2 (en) 2013-08-08 2019-03-12 Novan, Inc. Topical compositions and methods of using the same
US11813284B2 (en) 2013-08-08 2023-11-14 Novan, Inc. Topical compositions and methods of using the same
US10828323B2 (en) 2013-08-08 2020-11-10 Novan, Inc. Topical compositions and methods of using the same
US10322081B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
US11040006B2 (en) 2014-07-11 2021-06-22 Novan, Inc. Topical antiviral compositions, delivery systems, and methods of using the same
US10736839B2 (en) 2014-07-11 2020-08-11 Novan, Inc. Topical antiviral compositions, delivery systems, and methods of using the same
US11723858B2 (en) 2014-07-11 2023-08-15 Novan, Inc. Topical antiviral compositions, delivery systems, and methods of using the same
US10322082B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
US12054766B2 (en) 2014-08-20 2024-08-06 Neogen Food Safety Us Holdco Corporation Devices and methods for sample partitioning and analysis
US10912743B2 (en) 2016-03-02 2021-02-09 Novan, Inc. Compositions for treating inflammation and methods of treating the same
US11166980B2 (en) 2016-04-13 2021-11-09 Novan, Inc. Compositions, systems, kits, and methods for treating an infection
EP3713549B1 (en) * 2017-11-21 2024-06-19 LTS Lohmann Therapie-Systeme AG Transdermal therpeutic syste based on adhesive plasticizer-polymer-matrices

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