CA2500907A1 - Vehicle for topical delivery of anti-inflammatory compounds - Google Patents
Vehicle for topical delivery of anti-inflammatory compounds Download PDFInfo
- Publication number
- CA2500907A1 CA2500907A1 CA 2500907 CA2500907A CA2500907A1 CA 2500907 A1 CA2500907 A1 CA 2500907A1 CA 2500907 CA2500907 CA 2500907 CA 2500907 A CA2500907 A CA 2500907A CA 2500907 A1 CA2500907 A1 CA 2500907A1
- Authority
- CA
- Canada
- Prior art keywords
- set forth
- composition
- pharmaceutically active
- active component
- vehicle
- 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.)
- Abandoned
Links
Classifications
-
- 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
- A61K31/185—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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- 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
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A vehicle for topical application which contains a liquid eutectic mixture of hydrophobic compounds to improve solubility of pharmaceutically active component and enhance topical and transdermal delivery.
Description
VEHICLE FOR TOPICAL DELIVERY OF ANTI-INFI~AN~ATORY COMPOUNDS
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.
By including non-steroid anti-inflammatory drugs (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.
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
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.
By including non-steroid anti-inflammatory drugs (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.
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
2 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 (5-100), and 1-loo Indomethacin in alcohol. 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.
Generally, topical NSAID preparations do not have attributable side-effects such as gastric irritation and internal bleeding. Advantageously, 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 5-10s or greater, e.g., 5% Ibuprofen gel with isopropyl alcohol, to Indomethacin gel based on ethyl alcohol or even loo Indomethacin ointment with dimethylsulfoxide.
These solvents are widely used for gel preparation, but widespread use is often limited due to the proclivity for skin irritation. A further limitation is realized in fast termination of action for gel preparations since the
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 (5-100), and 1-loo Indomethacin in alcohol. 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.
Generally, topical NSAID preparations do not have attributable side-effects such as gastric irritation and internal bleeding. Advantageously, 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 5-10s or greater, e.g., 5% Ibuprofen gel with isopropyl alcohol, to Indomethacin gel based on ethyl alcohol or even loo Indomethacin ointment with dimethylsulfoxide.
These solvents are widely used for gel preparation, but widespread use is often limited due to the proclivity for skin irritation. A further limitation is realized in fast termination of action for gel preparations since the
3 drug precipitates from solution subsequent to water absorption from the body tissue. Further, solvents in high concentration often irritate the skin due to drying and delipidisation and may initiate contact dermatitis and allergy. The drug which is insoluble in water media and body fluids, precipitates in the upper skin layers and does not penetrate, thus seriously limiting the anti-inflammatory action. Similar behavior has been observed for polyethylene glycol (mixture of PEG-4000 and PEG-400) hydrophilic topical base compositions.
Traditional hydrophobic vehicles such as fixed oils, mineral oil, petrolatum, lanolin and wax based ointments, along with emulsion creams (either 0/W or W/0 type) are less irritating to human skin, but these present another complication - solubility. Drug loading in such vehicles is limited by the solubility of the drug in the lipid phase.
For example, the solubility of Indomethacin in olive or corn oil is below 0.20, whereas Ketoprofen is about 1.5%
and Piroxicam below 0.05%. According to Benita et at.
"Submicron Emulsions as Colloidal Drug Carriers for Intravenous Administration: Comprehensive Physicochemical Characterization", J. Pharm Sci., 1993, Nov. 82 (11), pp.
1069-79, even for low drug loading, stability of the dispersed system is questionable. A 0.1% Indomethacin submicron emulsion lost stability after 1 month storage.
Use of more polar hydrophobic compounds may help to improve solubility of NSAIDs. Tocopherol acetate, triethyl citrate, glycerin monolaurate, glycerin monooleate (MyverolTM 18-9) dissolve between 1.5 and 2 times more Indomethacin or Diclofenac (in acidic form). Nevertheless,
Traditional hydrophobic vehicles such as fixed oils, mineral oil, petrolatum, lanolin and wax based ointments, along with emulsion creams (either 0/W or W/0 type) are less irritating to human skin, but these present another complication - solubility. Drug loading in such vehicles is limited by the solubility of the drug in the lipid phase.
For example, the solubility of Indomethacin in olive or corn oil is below 0.20, whereas Ketoprofen is about 1.5%
and Piroxicam below 0.05%. According to Benita et at.
"Submicron Emulsions as Colloidal Drug Carriers for Intravenous Administration: Comprehensive Physicochemical Characterization", J. Pharm Sci., 1993, Nov. 82 (11), pp.
1069-79, even for low drug loading, stability of the dispersed system is questionable. A 0.1% Indomethacin submicron emulsion lost stability after 1 month storage.
Use of more polar hydrophobic compounds may help to improve solubility of NSAIDs. Tocopherol acetate, triethyl citrate, glycerin monolaurate, glycerin monooleate (MyverolTM 18-9) dissolve between 1.5 and 2 times more Indomethacin or Diclofenac (in acidic form). Nevertheless,
4 this loading is insufficient to obtain an effective NSAID
emulsion. Transdermal adhesive systems such as skin patches and plasters with Indomethacin or Diclofenac present low efficacy by the same reasoning.
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), Isopropylideneglycerin (SolketalTM), ethoxylated furanyl alcohol (GlucofurolTM) visibly boost drug implementing in the separate hydrophobic phase. However, upon mixing with water, most of the solvent is extracted into the water and the dissolved drug precipitates immediately and almost entirely from the oil phase.
Recently developed submicron emulsions (SME) employed as a base for NSAIDs, provide very effective delivery and exert pronounced improvement for drug action as discussed in Friedman et al. (United States Patent No. 6,113,921).
However, low solubility of NSAIDs in a lipid phase of such emulsions leads to shortened periods of efficacy and drug precipitation from the oil phase during storage. High loading, desirable for optimal activity of topical NSAID
preparation for SME is achievable only for highly lipophilic compounds, such as Naproxen, Ketoprofen or Ibuprofen with significantly lower anti-inflammatory activity.
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 50 of the oil phase, provides excellent stability and anesthetic action.
In view of the limitations in the anti-inflammatory
emulsion. Transdermal adhesive systems such as skin patches and plasters with Indomethacin or Diclofenac present low efficacy by the same reasoning.
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), Isopropylideneglycerin (SolketalTM), ethoxylated furanyl alcohol (GlucofurolTM) visibly boost drug implementing in the separate hydrophobic phase. However, upon mixing with water, most of the solvent is extracted into the water and the dissolved drug precipitates immediately and almost entirely from the oil phase.
Recently developed submicron emulsions (SME) employed as a base for NSAIDs, provide very effective delivery and exert pronounced improvement for drug action as discussed in Friedman et al. (United States Patent No. 6,113,921).
However, low solubility of NSAIDs in a lipid phase of such emulsions leads to shortened periods of efficacy and drug precipitation from the oil phase during storage. High loading, desirable for optimal activity of topical NSAID
preparation for SME is achievable only for highly lipophilic compounds, such as Naproxen, Ketoprofen or Ibuprofen with significantly lower anti-inflammatory activity.
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 50 of the oil phase, provides excellent stability and anesthetic action.
In view of the limitations in the anti-inflammatory
5 drug art, there exists a need for an improved composition which overcomes the shortcomings presently encountered.
It has been found that 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.
As a particular advantage, the eutectic mixture was found to be safe, non-toxic and present synergistic behavior in the anti-inflammatory action of NSAIDs due to the anti-inflammatory 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.
Prior to embracing on a discussion of the preparation, some general properties of menthol and camphor will be established.
The menthol used was (1R, 2S, 5R)-5-methyl-2-(1-methyethyl)-cyclohexanol with a molecular weight of 156.27 and melting point of 42°C. Menthol generally has a peppermint odor. It is well known as a skin irritant and
It has been found that 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.
As a particular advantage, the eutectic mixture was found to be safe, non-toxic and present synergistic behavior in the anti-inflammatory action of NSAIDs due to the anti-inflammatory 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.
Prior to embracing on a discussion of the preparation, some general properties of menthol and camphor will be established.
The menthol used was (1R, 2S, 5R)-5-methyl-2-(1-methyethyl)-cyclohexanol with a molecular weight of 156.27 and melting point of 42°C. Menthol generally has a peppermint odor. It is well known as a skin irritant and
6 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. This was established in the Handbook of Pharmaceutical Excipients, Third Edition, ed. A.H. Kibbe, Pharmaceutical Press, London, U.K., 2000, pp. 334-335.
Menthol has been used as mild local anesthetic and as volatile aromatic component for breath relief in obstruction and cold treatment in Hughes et al., (United States Patent No. 5,322,689).
Similar properties are known for camphor 1,7,7-trimethylbicyclo[2,2,1]heptanone-2, having a molecular weight of 152.24. Camphor has a high melting point (180°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.
Certain external analgesic products containing between 10% to 60o methyl salicylate, more than 3s to llo camphor and 1.25 to 16~ menthol, either singly or in combination,
Natural L-menthol exerts a cooling or refreshing sensation due to direct interaction with cold sensitive receptors in the skin. This was established in the Handbook of Pharmaceutical Excipients, Third Edition, ed. A.H. Kibbe, Pharmaceutical Press, London, U.K., 2000, pp. 334-335.
Menthol has been used as mild local anesthetic and as volatile aromatic component for breath relief in obstruction and cold treatment in Hughes et al., (United States Patent No. 5,322,689).
Similar properties are known for camphor 1,7,7-trimethylbicyclo[2,2,1]heptanone-2, having a molecular weight of 152.24. Camphor has a high melting point (180°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.
Certain external analgesic products containing between 10% to 60o methyl salicylate, more than 3s to llo camphor and 1.25 to 16~ menthol, either singly or in combination,
7 cause irritation or mild inflammation of the skin for the purpose of relieving pain in muscles, joints, or viscera distal to the site of application by stimulating depressing cutaneous sensory receptors, discussed in Ivy et al.
(United States Patent No. 5,013,726).
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.
These substances have been advertised for use in relieving joint pain, such as the elbow, knee, thumb area, ankle, neck, wrist, hand and finger, shoulder, etc.
To improve solubility of non-steroidal anti inflammatory drugs, a complex mixture of surfactants, polyglycol(s) and glycerides has been used in combination with polymers and sodium or potassium hydroxide solutions as established in Morton et al. (United States Patent No.
5, 376, 688 ) .
In Kaplun-Fischoff et al., "Testosterone Skin Permeation Enhancement by Menthol Through Formation of Eutectic with Drug and Interaction with Skin Lipids", J.
Pharm Sci. 1997,. December, 86 (12) pp. 1394-9, the g researchers observed that menthol forms a eutectic mixture with crystalline testosterone. The formed mixture is not liquid, but the composition demonstrated a significant improvement in transdermal penetration of testosterone.
According Kaplun-Frischoff et al., 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.
A careful investigation of existing compositions containing menthol and camphor in different ratios showed that there is no one example of the specific use of menthol and camphor in combination as eutectic mixture in order to improve solubility of an included drug. All anti-inflammatory components used in such formulations are liquid (methylsalycilate, benzylnicotinate, etc.) and easily miscible with oil components of the creams or ointments. There is no limitation for solubility, and these topicals can contain up to 60°s of active component, e.g., methylsalycilate), Altadonna (United States Patent No. 5,853,768).
In the documentation there has not been a recognition of a menthol-to-camphor ratio in the eutectic region. In all cases, the existing preparations are used only due to their mild irritative or anti-inflammatory activity (camphor, nicotinic acid derivatives) or skin penetration enhancement properties of menthol itself.
It has now been recognized that a radical increase of drug solubility in a eutectic mixture of polar hydrophobic compounds allows preparation of effective and safe topical formulations with these drugs for external application.
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.
In accordance with a further aspect of one embodiment of the present invention, there is provided 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.
Having thus described the invention, reference will now be made to the accompanying drawings illustrating preferred embodiments, and in which:
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 5 solubility in oleaginous vehicles and in a eutectic vehicle;
Figure 4 is a graphical representation of drug content change during storage; and Figure 5 is a graphical representation of comparative 10 anti-inflammatory activity of topical formulations.
A mixture of equimolar amounts of crystalline camphor and menthol at room temperature immediately led to liquefied crystals. This mixture was used in the preparations as an effective solvent for some NSAID
compounds.
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. 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. The maximum solubility in an equimolar eutectic menthol-camphor mixture is 160 mg/ml, compared with 2 mg/ml in the soy oil or 4.8 mg/ml in MCT oil. For comparison, Ho et. al. "Penetration Enhancement by Menthol Combined with a Solubilization Effect in a Mixed Solvent System", J. Controlled Release 1998, February 12; 51 (2-3), pp. 301-11, investigated the influence of menthol addition (up to 12% by weight) as solubility enhancer for Indomethacin in different pharmaceutical vehicles such as water, ethanol, propylene glycol and their combinations. In any case the maximum solubility hardly reached 2% (approximately 20 mg/ml).
In Figure 3, further graphic data are presented for Piroxicam.
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 60o menthol-camphor (1:1) content.
If 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).
Use of other ratios for menthol-camphor eutectic mixture (e. g., 2:1 or 1:2; 3:4 or 4:3) also improves solubility for most of the investigated substances, but to a slightly lower extent. Very significant improvement in solubility was achieved with replacement of menthol for another eutectic forming substance, thymol (2-isopropyl-5-methylphenol, thyme oil component).
Obtained solutions of NSAIDs in lipid phase containing menthol-camphor or another eutectic mixture vehicle are stable in wide temperature range and non-irritating for human and animal skin (Dreize' test). Based on these observations different topical formulations with NSAIDs were prepared and will now be discussed in the examples.
Example 1: Indomethacin 1~ cream TABhE 1 CREAM INGREDIENTS $
Indomethacin USP 1.00 2.5 Medium Chain Triglycerides (Labrafac~ 4.00 10 CCTG) Soy Lecithin (Phospholipon~ S-80) 1.00 2.5 () Camphor USP 3.00 7.5 L-(-)-Menthol USP 3.00 7,5 TweenTM-80 (Polysorbate 80, USP) 1.60 4.0 TPGS (Tocopherol polyethylene glycol 0.80 2.0 1000 succinate) Sodium Ethylenediamine tetraacetate 0.10 0.25 (EDTA sodium) Carbopol~ 971 P 1.50 3.75 Glycerin USP 2.50 6.25 Water 81.50 203.75 Vehicle (eutectic mixture) preparation:
(~) Camphor and L-Menthol were mixed together during heating at between 40 and 50°C until a clear liquid was obtained.
Oil phase preparation:
Soy lecithin, MCT oil and TPGS were mixed together at 45°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°C until completely dissolved.
Water phase preparation:
EDTA disodium salt, glycerin and TweenTM-80 were added to water (90% of calculated amount) and stirred until completely dissolved.
Emulsification:
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.
Cream preparation:
In a separate vessel Carbopol~ 971 P was mixed with 10% of calculated amount of water and soaked for between 2 and 6 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.
Example 2: Indomethacin 2~ cream The composition was prepared in accordance with the methodology of Example 1.
CREAM INGREDIENTS Per 100 Per 1000 Lipid Phase Indomethacin USP 2.00 20.00 Medium Chain Triglycerides 8.00 80.00 Egg Lecithin S-75 2.00 20.00 ~() Camphor USP 6.00 60.00 L-(-)-Menthol USP 6.00 60.00 TweenTM-80 (Pol sorbate-80 USP) 2.00 20.00 TPGS (Tocopherol polyethylene glycol 0.80 8.00 1000 succina Water Phase Sodium Ethylenediaminetetraacetate 0.10 1.00 Bronopol~ (2-Brom-2-nitro-1,3- 0.10 1.00 Triethanolamine 0.50 5.00 TM 0.50 5.00 Glycerin 2.20 22.00 Water ~ 69.80 698.00 Bronopol~ (2-Brom-2-nitro-1,3-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.
Example 3: Diclof~nac sodium 1~ cream The composition of the emulsion for 1% Diclofenac cream presented in Table 3. The cream contains approximately 140 of the oil phase with a ratio MCT:
Camphor: Menthol of 6:3:4.
Table 3. Emulsion part of Diclofenac sodium 1~ cream.
CREAM INGREDIENTS Per 100 g cream edium Chain Triglycerides (Labrafac~ CCTG) 6.00 () Camphor USP 3.00 L-(-)-Menthol USP 4.00 Tocopherol succinate 0.02 Soy Lecithin (Phospholipon~ S-80) 0.12 Tween-80 (Polysorbate - 80) 2.00 DICLOFENAC Sodium USP 1.00 ater 80.38 Hydrochloric acid 1N 3.5 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 5 sodium and TweenTM-80 in hot 85°C purified water.
After mixing the warm oil and hot water phases, hydrochloric acid was added to coarse emulsion while intensive stirring. The pH was adjusted to between 3.5 and 4.2. Homogenization was conducted as described in Example 10 2. After a fine emulsion was obtained, it was filtered through 0.45 micron PTFE membrane filter. The emulsion was used for cream preparation by addition of Carbopol~ 971 as a gelling agent to a final concentration of 1.5% with pH
adjustment to between 4.5 and 5Ø
15 1.5% 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 5o 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 260 of the oil phase with a ratio MCT: Camphor: Menthol of approximately 4.25:1:1.
_C_REAM INGREDIENTS _ Per 100 Per 300 Ibuprofen 5.00 15.00 Medium Chain Triglycerides 13.75 41.25 Soy Lecithin (Phospholipon~ S-80) 1.20 3.60 () Camphor USP 3.25 9.75 L-(-)-Menthol USP 3.25 9.75 TweenTM-80 (Polysorbate-80, USP) 2.00 6.00 TPGS (Tocopherol polyethylene glycol 0.80 2.40 1000 succinate) Sodium Ethylenediamine tetraacetate 0.10 0.30 (EDTA sodium) BronopolTM 0.10 0.30 Triethanolamine 1.00 3.00 Carbopol~ 934P 1.00 3.00 Glycerin 2.20 6.60 Water 66.35 398.10 Example 5: Piroxicam 0.55 cream The 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 280 of the oil phase with a ratio MCT:
Camphor: Thymol: Tocopherol acetate of approximately 2:5:5:2.
_. CREAM INGREDIENTS Per 100 Per 250 Piroxicam 2.00 5.00 Medium Chain Triglycerides 3.00 7.50 Soy Lecithin (Phospholipon~ S-80) 2.00 5.00 () Camphor USP 7.50 18.75 Thymol 7.50 18.75 TweenTM-80 (Polysorbate-80, USP) 2.50 6.25 Tocopherol acetate (Vitamine E 2.00 5.00 acetate) EDTA 0.10 0.25 Carbopol~ 934P 1.50 3.75 Glycerin 2.20 5.50 Triethanolamine 0.90 2.25 Water ~ 69.70 174.25 Example 6: Reference Emulsion with Indomethacin, prepared according to U.S.
Patent No. 6,113,921.
Per 100 cream 0.5~ Indo 1.0~ Indo CREAM INGREDIENTS (low (high 1 i a i Indomethacin 0.5 1.0 Medium Chain Triglycerides (MCT oil) 17.0 17.0 Egg Lecithin (Phospholipon~ E-80) 0.8 p,g Emulphor EL-620 (polyethoxylated 1.6 1.6 castor oil) Carbopol~ 940 1.7 1.7 Glycerin 2.2 2.2 EDTA sodium salt 0.05 0.05 Tocopherol acid succinate 0.04 0.05 Triethanolamine 0.65 0.65 Water 75.3 74.5 Indomethacin (0.5 g for low loading and 1.0 g for high loading emulsions) was dissolved in a preheated (60°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.
Further treatment of the emulsion was conducted in a high pressure homogenizer at 800 bar (12,000 psi) for 6 cycles. Thereafter, the emulsion was cooled to room temperature, and pH was adjusted to between 5.6 and 6.5.
Part of emulsion was gelled using Carbopol~ 940 to form a creamy another part was stored at room temperature in tightly closed amber glass containers for 6 months to observe the physical stability.
Example 7: Dialofeaac sodium 1.0$ and 1.5~ creams Diclofenac sodium (1.0% and 1.5s drug loading) emulsions were prepared as described in Example 3 and 3A.
To estimate drug precipitation, the stored emulsion samples either for the reference 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.
A low loaded emulsion, prepared in accordance with United States Patent No. 6,113,921, showed reasonable stability during storage, but with an increase in the initial Indomethacin loading, the final concentration of non-precipitated drug decreased drastically. In contrast, 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.
Example 8: Salicylic acid trolamine cream TABhE 7 Component Oil Phase Tocopherol acetate 3.0 (synth.) MyvacetTM 9-45K 9.0 (Quest) L-Menthol (USP) 2.0 DL-Camphor (USP) 2.0 Cremophor~ EL (BASF) 4.0 Supersat~ AWS (RITA) 2.0 Lecithin (Phosal 53 1.5 MCT) Ethyl alcohol 1.5 Estol~ 1540 3.0 (Ethylhexyl Cocoate, Uniquema) Crotix~ (Croda) 2.0 Surfhope~ C-1601 2.0 (Mitsubishi) Surfhope~ C-1816 (75- 2.0 25) (Mitsubishi) Salicylic acid 7.30 Water phase Triethanolamine USP/NF 7.70 BronopolTM (BASF) 0.10 Water purified 50.90 Total 100.00 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":
Investigations on animals (rats, carrageenan induced paw edema model) showed significant anti-inflammatory action of the topically applied compositions containing the 5 eutectic vehicle. The results are illustrated in Figure 5.
From a review of Figure 5, it is evident that the anti inflammatory efficacy of the formulations of the present invention (ARX) is superior. This is a consequential result of the increased solubility and thus amount of the active 10 ingredient.
Area Under the Curve (AUC) ratio for edema volume (calculated by trapezoidal rule for t=0-6 hours).
GROUP __ Ratio t RSD
~~~ , %
Control _ 28%) (nontreated) _______ 100%
~~ ( Indomethacin cream (ex. 2 ) 32 % 12 ( %
) 2 mg of Indomethacin/rat Indomethacin gel (MethacinTM, Sumitomo Pharm.) 114%( 39%) 2 mg of Indomethacin/rat Diclofenac sodium cream (ex. 3) 30% ( 14%) 2 mg of Diclofenac sodium / rat Voltaren~ Emulgel~ 82%( 9%) 2 mg of Diclofenac / rat Salicylic acid trolamin cream (ex. 8) 65%( 18%) (15 mg of salicylate/rat) Marketed Trolamine Salicylate cream (Aspercream) 89% ( 42%) (15 mg of salicylate/rat) 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%. According to table 8 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 50o higher anti s inflammatory activity.
Although embodiments of the invention have been described above, it is not limited thereto and it will be apparent to those skilled in the art that numerous modifications form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
(United States Patent No. 5,013,726).
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.
These substances have been advertised for use in relieving joint pain, such as the elbow, knee, thumb area, ankle, neck, wrist, hand and finger, shoulder, etc.
To improve solubility of non-steroidal anti inflammatory drugs, a complex mixture of surfactants, polyglycol(s) and glycerides has been used in combination with polymers and sodium or potassium hydroxide solutions as established in Morton et al. (United States Patent No.
5, 376, 688 ) .
In Kaplun-Fischoff et al., "Testosterone Skin Permeation Enhancement by Menthol Through Formation of Eutectic with Drug and Interaction with Skin Lipids", J.
Pharm Sci. 1997,. December, 86 (12) pp. 1394-9, the g researchers observed that menthol forms a eutectic mixture with crystalline testosterone. The formed mixture is not liquid, but the composition demonstrated a significant improvement in transdermal penetration of testosterone.
According Kaplun-Frischoff et al., 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.
A careful investigation of existing compositions containing menthol and camphor in different ratios showed that there is no one example of the specific use of menthol and camphor in combination as eutectic mixture in order to improve solubility of an included drug. All anti-inflammatory components used in such formulations are liquid (methylsalycilate, benzylnicotinate, etc.) and easily miscible with oil components of the creams or ointments. There is no limitation for solubility, and these topicals can contain up to 60°s of active component, e.g., methylsalycilate), Altadonna (United States Patent No. 5,853,768).
In the documentation there has not been a recognition of a menthol-to-camphor ratio in the eutectic region. In all cases, the existing preparations are used only due to their mild irritative or anti-inflammatory activity (camphor, nicotinic acid derivatives) or skin penetration enhancement properties of menthol itself.
It has now been recognized that a radical increase of drug solubility in a eutectic mixture of polar hydrophobic compounds allows preparation of effective and safe topical formulations with these drugs for external application.
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.
In accordance with a further aspect of one embodiment of the present invention, there is provided 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.
Having thus described the invention, reference will now be made to the accompanying drawings illustrating preferred embodiments, and in which:
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 5 solubility in oleaginous vehicles and in a eutectic vehicle;
Figure 4 is a graphical representation of drug content change during storage; and Figure 5 is a graphical representation of comparative 10 anti-inflammatory activity of topical formulations.
A mixture of equimolar amounts of crystalline camphor and menthol at room temperature immediately led to liquefied crystals. This mixture was used in the preparations as an effective solvent for some NSAID
compounds.
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. 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. The maximum solubility in an equimolar eutectic menthol-camphor mixture is 160 mg/ml, compared with 2 mg/ml in the soy oil or 4.8 mg/ml in MCT oil. For comparison, Ho et. al. "Penetration Enhancement by Menthol Combined with a Solubilization Effect in a Mixed Solvent System", J. Controlled Release 1998, February 12; 51 (2-3), pp. 301-11, investigated the influence of menthol addition (up to 12% by weight) as solubility enhancer for Indomethacin in different pharmaceutical vehicles such as water, ethanol, propylene glycol and their combinations. In any case the maximum solubility hardly reached 2% (approximately 20 mg/ml).
In Figure 3, further graphic data are presented for Piroxicam.
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 60o menthol-camphor (1:1) content.
If 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).
Use of other ratios for menthol-camphor eutectic mixture (e. g., 2:1 or 1:2; 3:4 or 4:3) also improves solubility for most of the investigated substances, but to a slightly lower extent. Very significant improvement in solubility was achieved with replacement of menthol for another eutectic forming substance, thymol (2-isopropyl-5-methylphenol, thyme oil component).
Obtained solutions of NSAIDs in lipid phase containing menthol-camphor or another eutectic mixture vehicle are stable in wide temperature range and non-irritating for human and animal skin (Dreize' test). Based on these observations different topical formulations with NSAIDs were prepared and will now be discussed in the examples.
Example 1: Indomethacin 1~ cream TABhE 1 CREAM INGREDIENTS $
Indomethacin USP 1.00 2.5 Medium Chain Triglycerides (Labrafac~ 4.00 10 CCTG) Soy Lecithin (Phospholipon~ S-80) 1.00 2.5 () Camphor USP 3.00 7.5 L-(-)-Menthol USP 3.00 7,5 TweenTM-80 (Polysorbate 80, USP) 1.60 4.0 TPGS (Tocopherol polyethylene glycol 0.80 2.0 1000 succinate) Sodium Ethylenediamine tetraacetate 0.10 0.25 (EDTA sodium) Carbopol~ 971 P 1.50 3.75 Glycerin USP 2.50 6.25 Water 81.50 203.75 Vehicle (eutectic mixture) preparation:
(~) Camphor and L-Menthol were mixed together during heating at between 40 and 50°C until a clear liquid was obtained.
Oil phase preparation:
Soy lecithin, MCT oil and TPGS were mixed together at 45°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°C until completely dissolved.
Water phase preparation:
EDTA disodium salt, glycerin and TweenTM-80 were added to water (90% of calculated amount) and stirred until completely dissolved.
Emulsification:
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.
Cream preparation:
In a separate vessel Carbopol~ 971 P was mixed with 10% of calculated amount of water and soaked for between 2 and 6 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.
Example 2: Indomethacin 2~ cream The composition was prepared in accordance with the methodology of Example 1.
CREAM INGREDIENTS Per 100 Per 1000 Lipid Phase Indomethacin USP 2.00 20.00 Medium Chain Triglycerides 8.00 80.00 Egg Lecithin S-75 2.00 20.00 ~() Camphor USP 6.00 60.00 L-(-)-Menthol USP 6.00 60.00 TweenTM-80 (Pol sorbate-80 USP) 2.00 20.00 TPGS (Tocopherol polyethylene glycol 0.80 8.00 1000 succina Water Phase Sodium Ethylenediaminetetraacetate 0.10 1.00 Bronopol~ (2-Brom-2-nitro-1,3- 0.10 1.00 Triethanolamine 0.50 5.00 TM 0.50 5.00 Glycerin 2.20 22.00 Water ~ 69.80 698.00 Bronopol~ (2-Brom-2-nitro-1,3-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.
Example 3: Diclof~nac sodium 1~ cream The composition of the emulsion for 1% Diclofenac cream presented in Table 3. The cream contains approximately 140 of the oil phase with a ratio MCT:
Camphor: Menthol of 6:3:4.
Table 3. Emulsion part of Diclofenac sodium 1~ cream.
CREAM INGREDIENTS Per 100 g cream edium Chain Triglycerides (Labrafac~ CCTG) 6.00 () Camphor USP 3.00 L-(-)-Menthol USP 4.00 Tocopherol succinate 0.02 Soy Lecithin (Phospholipon~ S-80) 0.12 Tween-80 (Polysorbate - 80) 2.00 DICLOFENAC Sodium USP 1.00 ater 80.38 Hydrochloric acid 1N 3.5 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 5 sodium and TweenTM-80 in hot 85°C purified water.
After mixing the warm oil and hot water phases, hydrochloric acid was added to coarse emulsion while intensive stirring. The pH was adjusted to between 3.5 and 4.2. Homogenization was conducted as described in Example 10 2. After a fine emulsion was obtained, it was filtered through 0.45 micron PTFE membrane filter. The emulsion was used for cream preparation by addition of Carbopol~ 971 as a gelling agent to a final concentration of 1.5% with pH
adjustment to between 4.5 and 5Ø
15 1.5% 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 5o 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 260 of the oil phase with a ratio MCT: Camphor: Menthol of approximately 4.25:1:1.
_C_REAM INGREDIENTS _ Per 100 Per 300 Ibuprofen 5.00 15.00 Medium Chain Triglycerides 13.75 41.25 Soy Lecithin (Phospholipon~ S-80) 1.20 3.60 () Camphor USP 3.25 9.75 L-(-)-Menthol USP 3.25 9.75 TweenTM-80 (Polysorbate-80, USP) 2.00 6.00 TPGS (Tocopherol polyethylene glycol 0.80 2.40 1000 succinate) Sodium Ethylenediamine tetraacetate 0.10 0.30 (EDTA sodium) BronopolTM 0.10 0.30 Triethanolamine 1.00 3.00 Carbopol~ 934P 1.00 3.00 Glycerin 2.20 6.60 Water 66.35 398.10 Example 5: Piroxicam 0.55 cream The 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 280 of the oil phase with a ratio MCT:
Camphor: Thymol: Tocopherol acetate of approximately 2:5:5:2.
_. CREAM INGREDIENTS Per 100 Per 250 Piroxicam 2.00 5.00 Medium Chain Triglycerides 3.00 7.50 Soy Lecithin (Phospholipon~ S-80) 2.00 5.00 () Camphor USP 7.50 18.75 Thymol 7.50 18.75 TweenTM-80 (Polysorbate-80, USP) 2.50 6.25 Tocopherol acetate (Vitamine E 2.00 5.00 acetate) EDTA 0.10 0.25 Carbopol~ 934P 1.50 3.75 Glycerin 2.20 5.50 Triethanolamine 0.90 2.25 Water ~ 69.70 174.25 Example 6: Reference Emulsion with Indomethacin, prepared according to U.S.
Patent No. 6,113,921.
Per 100 cream 0.5~ Indo 1.0~ Indo CREAM INGREDIENTS (low (high 1 i a i Indomethacin 0.5 1.0 Medium Chain Triglycerides (MCT oil) 17.0 17.0 Egg Lecithin (Phospholipon~ E-80) 0.8 p,g Emulphor EL-620 (polyethoxylated 1.6 1.6 castor oil) Carbopol~ 940 1.7 1.7 Glycerin 2.2 2.2 EDTA sodium salt 0.05 0.05 Tocopherol acid succinate 0.04 0.05 Triethanolamine 0.65 0.65 Water 75.3 74.5 Indomethacin (0.5 g for low loading and 1.0 g for high loading emulsions) was dissolved in a preheated (60°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.
Further treatment of the emulsion was conducted in a high pressure homogenizer at 800 bar (12,000 psi) for 6 cycles. Thereafter, the emulsion was cooled to room temperature, and pH was adjusted to between 5.6 and 6.5.
Part of emulsion was gelled using Carbopol~ 940 to form a creamy another part was stored at room temperature in tightly closed amber glass containers for 6 months to observe the physical stability.
Example 7: Dialofeaac sodium 1.0$ and 1.5~ creams Diclofenac sodium (1.0% and 1.5s drug loading) emulsions were prepared as described in Example 3 and 3A.
To estimate drug precipitation, the stored emulsion samples either for the reference 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.
A low loaded emulsion, prepared in accordance with United States Patent No. 6,113,921, showed reasonable stability during storage, but with an increase in the initial Indomethacin loading, the final concentration of non-precipitated drug decreased drastically. In contrast, 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.
Example 8: Salicylic acid trolamine cream TABhE 7 Component Oil Phase Tocopherol acetate 3.0 (synth.) MyvacetTM 9-45K 9.0 (Quest) L-Menthol (USP) 2.0 DL-Camphor (USP) 2.0 Cremophor~ EL (BASF) 4.0 Supersat~ AWS (RITA) 2.0 Lecithin (Phosal 53 1.5 MCT) Ethyl alcohol 1.5 Estol~ 1540 3.0 (Ethylhexyl Cocoate, Uniquema) Crotix~ (Croda) 2.0 Surfhope~ C-1601 2.0 (Mitsubishi) Surfhope~ C-1816 (75- 2.0 25) (Mitsubishi) Salicylic acid 7.30 Water phase Triethanolamine USP/NF 7.70 BronopolTM (BASF) 0.10 Water purified 50.90 Total 100.00 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":
Investigations on animals (rats, carrageenan induced paw edema model) showed significant anti-inflammatory action of the topically applied compositions containing the 5 eutectic vehicle. The results are illustrated in Figure 5.
From a review of Figure 5, it is evident that the anti inflammatory efficacy of the formulations of the present invention (ARX) is superior. This is a consequential result of the increased solubility and thus amount of the active 10 ingredient.
Area Under the Curve (AUC) ratio for edema volume (calculated by trapezoidal rule for t=0-6 hours).
GROUP __ Ratio t RSD
~~~ , %
Control _ 28%) (nontreated) _______ 100%
~~ ( Indomethacin cream (ex. 2 ) 32 % 12 ( %
) 2 mg of Indomethacin/rat Indomethacin gel (MethacinTM, Sumitomo Pharm.) 114%( 39%) 2 mg of Indomethacin/rat Diclofenac sodium cream (ex. 3) 30% ( 14%) 2 mg of Diclofenac sodium / rat Voltaren~ Emulgel~ 82%( 9%) 2 mg of Diclofenac / rat Salicylic acid trolamin cream (ex. 8) 65%( 18%) (15 mg of salicylate/rat) Marketed Trolamine Salicylate cream (Aspercream) 89% ( 42%) (15 mg of salicylate/rat) 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%. According to table 8 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 50o higher anti s inflammatory activity.
Although embodiments of the invention have been described above, it is not limited thereto and it will be apparent to those skilled in the art that numerous modifications form part of the present invention insofar as they do not depart from the spirit, nature and scope of the claimed and described invention.
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A vehicle for topical delivery of a pharmaceutically active component, comprising a liquid eutectic mixture containing a hydrophobic component.
2. The vehicle as set forth in claim 1, wherein said hydrophobic component is selected from the group consisting of pharmaceutically acceptable glycerin esters, aliphatic esters, aromatic esters, waxes, lipids, fats, lipid soluble vitamins, hydrocarbons, silicone polymers, tocopherols, tocotrienols and related compounds, or mixture thereof.
3. The vehicle as set forth in claims 1 or 2, wherein the ratio of said hydrophobic component and liquid eutectic mixture are in a ratio of between 1:10 to 10:1.
4. The vehicle as set forth in any one of claims 1 through 3, wherein the ratio of said hydrophobic component and liquid eutectic mixture are in a ratio of between 1:3 to 3:1.
5. The vehicle as set forth in any one of claims 1 through 4, wherein said eutectic mixture comprises at least two compounds selected from the group consisting of camphor, menthol, thymol, resorcinol, phenol or substituted phenol derivativesThe vehicle as set forth claim 5, wherein said eutectic mixture is liquid at ambient temperature.
6. A composition for topical delivery comprising an oil-in-water or water-in-oil emulsion or microemulsion, wherein the oil phase of said emulsion comprises a vehicle as set forth in claim 3.
7. The composition as set forth in claim 6, wherein said pharmaceutically active component is dissolved in said oil phase of said emulsion or microemulsion.
8. The composition as set forth in any one of claims 6 or 7, wherein said oil phase comprises between 5% and 80% of said composition.
9. The composition as set forth in any one of claims 6 through 8, further including a surfactant.
10. The composition as set forth in any one of claims 6 through 9, wherein said pharmaceutically active component is selected from anti-inflammatory drugs.
11. The composition as set forth in claim 10, wherein said anti-inflammatory drugs are selected from group of non-steroidal anti-inflammatory drugs (NSAIDs).
12. The composition as set forth in claims 10 or 11, wherein said anti-inflammatory drugs are selected from the group consisting of indomethacin, diclofenac, ketorolac, piroxicam, meloxicam, tenoxicam, ketoprofen, flurbiprofen, ibuprofen, nimesulide, naproxen, rofecoxib, celecoxib and salicylic acid.
13. The composition as set forth in any one of claims 6 through 12, further including additional pharmaceutically active components, pharmaceutically acceptable surfactants, viscosity regulating agents, antibacterial preservatives, skin penetration enhancers, fragrances and colorants.
14. The composition as set forth in any one of claims 9 through 13, wherein said surfactant is non-ionic surfactant, phospholipid or mixture thereof.
15. A method for increasing the solubility of a pharmaceutically active component in a vehicle for topical delivery of said 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 said pharmaceutically active component and said at least two members whereby said mixture contains a greater amount of solubilzed active component relative to a non eutectic mixture.
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 said pharmaceutically active component and said at least two members whereby said mixture contains a greater amount of solubilzed active component relative to a non eutectic mixture.
16. The method as set forth in claim 15, wherein said two selected compounds are camphor and menthol.
17. The method as set forth in claims 15 or 16, wherein said pharmaceutically active component comprises a non steroidal anti-inflammatory drug (NSAID).
18. A composition for topical delivery having an increased amount of a solubilized pharmaceutically active component comprising an emulsion selected from the group consisting of an oil-in-water, water-in-oil and microemulsion, wherein said oil phase of said emulsion comprises a vehicle as set forth in claim 3, wherein said hydrophobic component is selected from the group consisting of pharmaceutically acceptable glycerin esters, aliphatic esters, aromatic esters, waxes, lipids, fats, lipid soluble vitamins, hydrocarbons, silicone polymers, tocopherols, tocotrienols and related compounds, or mixture thereof, said eutectic;
mixture comprising at least two members selected from the group consisting of camphor, menthol, thymol, resorcinol, phenol or substituted phenol derivatives; and a pharmaceutically active component, said composition having an increased solubilized amount of said pharmaceutically active component relative to a non eutectic composition.
mixture comprising at least two members selected from the group consisting of camphor, menthol, thymol, resorcinol, phenol or substituted phenol derivatives; and a pharmaceutically active component, said composition having an increased solubilized amount of said pharmaceutically active component relative to a non eutectic composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2500907 CA2500907A1 (en) | 2005-03-15 | 2005-03-15 | Vehicle for topical delivery of anti-inflammatory compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2500907 CA2500907A1 (en) | 2005-03-15 | 2005-03-15 | Vehicle for topical delivery of anti-inflammatory compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2500907A1 true CA2500907A1 (en) | 2006-09-15 |
Family
ID=36998156
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2500907 Abandoned CA2500907A1 (en) | 2005-03-15 | 2005-03-15 | Vehicle for topical delivery of anti-inflammatory compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2500907A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009147269A1 (en) | 2008-06-06 | 2009-12-10 | Laboratorios Alcalá Farma, S.L. | Topical ibuprofen formulation |
| WO2010072958A3 (en) * | 2008-12-23 | 2012-01-12 | Galderma S.A. | Topical pharmaceutical composition containing a water-sensitive active principle |
| US9084754B2 (en) | 2009-12-23 | 2015-07-21 | Nuvo Research Inc. | Highly permeating terbinafine formulation |
| CN114259461A (en) * | 2021-11-29 | 2022-04-01 | 海南全星制药有限公司 | Diclofenac sodium gel and preparation method thereof |
| CN114577952A (en) * | 2022-04-13 | 2022-06-03 | 河南师范大学 | Method for enriching and determining antiviral drug famciclovir residue in environmental water sample based on hydrophobic eutectic solvent liquid-liquid microextraction |
| CN115916183A (en) * | 2020-01-10 | 2023-04-04 | 布里奥里生物技术公司 | Topical compositions containing rofecoxib and methods of making and using the same |
-
2005
- 2005-03-15 CA CA 2500907 patent/CA2500907A1/en not_active Abandoned
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009147269A1 (en) | 2008-06-06 | 2009-12-10 | Laboratorios Alcalá Farma, S.L. | Topical ibuprofen formulation |
| WO2010072958A3 (en) * | 2008-12-23 | 2012-01-12 | Galderma S.A. | Topical pharmaceutical composition containing a water-sensitive active principle |
| EP2419082B1 (en) * | 2008-12-23 | 2020-01-22 | Galderma S.A. | Topical pharmaceutical composition containing a water-sensitive active principle |
| US9084754B2 (en) | 2009-12-23 | 2015-07-21 | Nuvo Research Inc. | Highly permeating terbinafine formulation |
| CN115916183A (en) * | 2020-01-10 | 2023-04-04 | 布里奥里生物技术公司 | Topical compositions containing rofecoxib and methods of making and using the same |
| CN114259461A (en) * | 2021-11-29 | 2022-04-01 | 海南全星制药有限公司 | Diclofenac sodium gel and preparation method thereof |
| CN114259461B (en) * | 2021-11-29 | 2023-09-12 | 海南全星制药有限公司 | Diclofenac sodium gel and preparation method thereof |
| CN114577952A (en) * | 2022-04-13 | 2022-06-03 | 河南师范大学 | Method for enriching and determining antiviral drug famciclovir residue in environmental water sample based on hydrophobic eutectic solvent liquid-liquid microextraction |
| CN114577952B (en) * | 2022-04-13 | 2023-08-04 | 河南师范大学 | Method for determining antiviral drug famciclovir residue in environmental water sample based on hydrophobic eutectic solvent liquid-liquid microextraction enrichment |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7781429B2 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| US20060241175A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| WO2006096955A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| US11123315B2 (en) | Topical compositions for pain relief, manufacture and use | |
| RU2754846C1 (en) | Local anaesthetic compositions | |
| US11666531B2 (en) | Delivery system | |
| JP5052558B2 (en) | Gel ointment | |
| JP4549006B2 (en) | Gel ointment | |
| JP2010521442A (en) | Topical formulation | |
| CN106572970B (en) | Novel gel for topical administration of non-steroidal anti-inflammatory drugs for relief of musculoskeletal pain and method of making same | |
| CA2500907A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| JP2012092067A (en) | Nonsteroidal anti-inflammatory analgesic agent for external use | |
| EA029402B1 (en) | Transdermal agent for treating and preventing joint and soft tissue diseases, combined transdermal preparation for treating and preventing joint and soft tissue diseases and method for production thereof | |
| KR101894891B1 (en) | Topical gel composition containing dexibuprofen emulsion with enhaced permeability | |
| KR20190101140A (en) | Pharmaceutical composition for forming film comprising NSAID | |
| JP2935113B1 (en) | Indomethacin transdermal absorbent | |
| KR20240029152A (en) | Method for preparing an external gel formulation containing propionic acid-based nonsteroidal drug as an active ingredient that can be used for the treatment of itchiness | |
| JPH11343248A (en) | Composition for locally targeting use | |
| US20230302028A1 (en) | Pain-relieving topical compositions | |
| WO2020086038A2 (en) | Topical compositions comprising tolperisone and selective cox-2 inhibitor combination | |
| TR2021007476A2 (en) | TOPICAL COMPOSITIONS CONTAINING INDOMETHACINE IN COMBINATION WITH MUSCLE RELAXANT AGENTS | |
| KR20200004277A (en) | Pharmaceutical composition for forming film comprising NSAID |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20120315 |