Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

• transmucosal absorption In such a system the drug is solubilized either in the oil or water phase, in presence of physiologically acceptable surfactants and cosurfactants, and wherein in certain condition the cosurfactant can assume the function of the oil, or the last can act as surfactant.
• the topical administration for systemic use (via transdermal) of ionic drugs can benefit from biphasic compositions of different kinds, among which the above described microemulsions.
• Swiss Patent Appl. CH-86-2597/86 8 (Ciba -Geigy), describes in general, some compositions (such us cream, ointment and gel) which however do not include microemulsions, in particular refers to the anionic drug Diclofenac or its salts (sodic, potassium salt, diethylammonium salt).
• microemulsions An important limit to these biphasical compositions called "microemulsions" is represented by the necessity of formulating the composition according to definite percentages rate of component substances, as shown from diagrams of pseudo- ternary phase.
• This relative composition, that allows the forming of the liquid system, anisotropic and transparent, defined as “microemulsion” is essentially not modifiable because the addition or the substraction of one of the four components (l-IV) out of the component concentration limits will alterate the system, with separation of phases and destruction of the system itself, while substitution of one of the components will originate a system with different characteristics.
• absorption or transdermal permeation of an active principle, released from microemulsion depends on the composition of the system itself: the dissolved drug will partition itself into the two phases, oil (lipophilic) and water (hydrophilic), in relation to its coefficient of oil/water partitioning. Permeation rate and absorption of drug is therefore determined by the composition and the possibility of modifying such a rate without changing completely the composition of the microemulsion results virtually not realizable.
• the present invention refers to a drug multicomponent biphasical composition that enables to solve the problems of prior art.
• the present invention refers to a drug composition consisting of an oil phase and a water phase, comprising typically four essential components, defined as (I) dispersed or internal phase, (II) dispersing or external phase, (III) surfactant and (IV) cosurfactant, mixed together in molar ratios determined by the pseudo-ternary phase diagrams and moreover containing a drug (V) and characterized in that it furtherly comprises one compound (VI) able to modify the partitioning coefficient of the drug between oil and water phase, consequently influencing the rate of permeation through the skin.
• the compound (VI) can, in some unexpected cases, form specific complexes with the drug modifying its concentration in the phases of the biphasic system and directly influencing transdermal permeation of the drug itself.
• Figure 1 represents the phase diagram in aqueous solution of the salt of hydroxyethyl pyrrolidine of diclofenac (DIEP) and N-methyl pyrrolidone (NMP).
• Figure 2 represents the phase diagram in aqueous solution of the sodium salt of diclofenac and N-methyl pyrrolidone (NMP).
• Figure 3 represents the phase diagram in aqueous solution of acyclovir (ACY) and N-methyl pyrrolidone (NMP).
• Figure 4 represents the surface tension of DIEP aqueous solutions in the presence of different concentrations of NMP (% by volume).
• Figure 5 represents the transdermal permeation of hydroxyethyl pyrrolidone diclofenac in the formulation I of example 1 (curve (A)) in comparison with formulation A of the example 7 (curve (B)).
• Figure 6 represents the transdermal permeation of sodium diclofenac in the formulation V of the example 1 (curve (A)) in comparison with the formulation B of the example 7 (curve (B)).
• Figure 7 represents the transdermal permeation of the papaverin HCI in the formulation XII of the example 1 (curve (A)) in comparison with formulation C of the example 7 (curve (B)).
• Figure 8 represents the transdermal permeation of nimesulide according to the formulation XIV of the example 1 (curve (A)) in comparison with the formulation D of the example 7 (curve (B)).
• Figure 9 represents the transdermal permeation of acyclovir of the formulation XVI of the example 1 (curve (A)) in comparison with the formulation E of the example
• Figure 10 represents the transdermal permeation rate (flow) and the partition factors (P m )of hydroxyethyl pyrrolidine diclofenac (DIEP) of the formulations I, II,
• Figure 11 represents the transdermal permeation rate (flow) and the partition factors (P m ) of (DIEP) of the formulations VIII, IX, x and XI of the example 1 containing propylene glycol (PG) in comparison with the formulation (A) without PG.
• the invention refers to a pharmaceutical composition mainly, but not only, applicable to topical and systemic administration of drugs by transdermal route.
• the composition allows improvement in both skin layer absorption and transdermal permeation of ionic and non-ionic drugs.
• the present invention describes a multicomponent biphasic composition comprising typically four essential components, defined as (I) dispersed or internal phase, (II) dispersing or external phase, (III) surfactant and (IV) cosurfactant, mixed together in molar ratios determined by the pseudo-ternary phase diagrams and moreover containing a drug (V) and a compound (VI), generally but not necessarily of amphyfilic and non-ionic type, able to modify the drug partition coefficient between oil phase and water phase and consequently rate of transdermal permeation of the drug itself.
• the compound (VI) can, in some unexpected cases, form specific complexes with the drug modifying its concentration in biphasic system phases and directly influencing transdermal permeation of the drug itself.
• the components can be three because the component (I) or (II) can also act as cosurfactant (IV); more often they are more than four.
• cosurfactant (IV) can contribute to form the composition taking the place of the surfactant (III) or the cosurfactant (IV).
• Both internal phase and external phase can be defined as “oil phase” and “aqueous phase", generating multicomponent systems "oil in water” or "water in oil”.
• oil phase is made of lipofilic liquids unable to mix with water as organic solvents, oils and fats
• water phase is made up by polar liquids, hydrofilic and normally mixable with water.
• An important advantage of the invention is the possibility to improve transdermal permeation of active principles both hydrosoluble (for example diclofenac salts) and lipofilic and scarcely soluble in water (for example papaverine and progesterone) thanks to the possibility to modify the partitioning of the active principle itself between the oil and water phases thanks to the presence of compounds (VI) that modify the partitioning coefficient.
• the biphasic multicomponent composition according to the invention includes:
• oil phase one or more lipophylic or oil carriers, called “oil phase”, phyisiologically and pharmaceutically acceptable
• water phase one or more hydrofilic or water carriers, called “water phase”, physiologically and pharmaceutically acceptable
• surfactant (III) of ionic or non-ionic type
• cosurfactant preferably but not necessarily chosen among alcohols or short aliphatic chain acids
• an active principle for pharmaceutical use (V), in enough quantity or concentration for the therapeutic effect desired; 6) one component, preferably but non necessarily amphyfilic (VI), called “partition modifier”, able to modify active principle partitioning between oil phase and water phase.
• compositions that can benefit from the invention are the one used for long-term treatments, like for example non-steroidal anti- inflammatories (NSAID), estrogen or progestins, cardiovasculars, antiviral, antimicotic, antitumoral hormons.
• NSAID non-steroidal anti- inflammatories
• usable active principles can be relatively hydrosoluble (for example diclofenac salts) or liposoluble (for example estradiol, progesterone), or also scarcely soluble in both carriers (for example acyclovir).
• Analgesic and non-steroidal anti-inammatories and their salts diclofenac sodium, hydroxyethyl pyrrolidine diclofenac, diethylammine diclofenac, ibuprofen, flurbiprofen, ketoprofen, idometacina , mefenamic acid, naproxene, nimesulide, piroxicam.
• Antiarithmics amiodarone, diisopyramide, verapamil, propranolol.
• Antibacterials amoxicillin, flucloxacillin, gentamicin, rifampicin, erythromicine, cephalosporin .
• Antimicotic amfotericin, buconazol nitrate, ketoconazol, econazol, fluconazolo, flucitosina, griseofulvine. itraconazol, miconazol, rystatin, sulconazol, tioconazol.
• Antivirals acyclovir, gancyclovir, AZT, proteasi inhibitor.
• Anti-Hypertensives amlodipine, clonidine, diltiazem, felodipine, guanabenz acetate, isradipine, minoxidil, chloride nicardipine, nifedipine, chloride prazosin, papaverine.
• Antidepressives carbamazepine.
• Antihistaminic difenidramine, chlorfeniramine, chlorciclizine, prometazin, acrivastine, loratadine, terfenadine.
• Antitumoral and immunogenic cyclosporine, decarbazine, etoposide, lomustine, melphalan, mitomicin, mitoanthrone, procarbazine, taxol and derivatives.
• ⁇ -Blockers alprenolol, atenolol, oxprenolol, pindolol, propranolol.
• ⁇ -Agonists salbutamol, salmeterol.
• Cardiac inotropics and cardiovascolars amrinone, digitoxinn, digoxin, lanatoside
• Corticosteroids bechlomethasone, betamethasone, budesonide, cortisone acetate, desossimetasone, dexamethasone, fludrocortidone acetate, flunisolide, hydrocortisone, methylprednisolone, prednisone, triamicinolone.
• Gastrointestinals and anti H 2 -histaminics cimetidine, cisapride, domperidone, famotidine, loperamide, mesalazine, omeprazol, ondansetron, ranitidine chloride.
• Hypolipemics bezafibrate, chlorofibrate, gemfibrozil, probucol.
• Anti-Angina amil nitrate, gliceryltrinitrate, isosorbide dinitrate and mononitrate, pentaeritritol tetranitrate.
• Vitamins and nutritional agents betacarothene, vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K.
• Analgesic Opioids codeine, destropropoxifene, dihydrocodeine, morphine, pentazocine, metadone.
• Sexual hormons danazol, ethynilestradiol, medroxyiprogesterone acetato, methyltestosterone, testosterone, noretistrone, norgestrel, estradiolo, estriolo, progesterone, stilbestrolo, diethylstilbestrol.
• Peptidic molecules with different activity for example LH-RH analogous, calcitonine, glutathione.
• Molecules with specific topical activity for example sun protectants (UV absorbent) skin nourishing, glycoiic acid.
• Active principles that can particolariy benefit from the invention are for example non- steroidal anti-inflammatories (diclofenac, diclofenac sodium, diclofenac hydroxyethyl pyrrolidine, nimesulide), steroids (progesterone, estradiol, medroxyprogesterone acetate), different cardiovasculars (nifedipine, papaverine, diltiazem, verapamil), antivirals (acyclovir), antimicotic (ketoconazol, itraconazol).
• oil carriers can be mentioned both natural products and synthetic or semsynthetic products called “oils” because not mixable or only partially mixable with water. All components can be used alone or, if possible, in mixtures with different percentages.
• oil components which can be used as dispersed phase (I), but also as dispersing phase (II) 1) saturated and unsaturated natural oils: olive oil, peanuts, soy, Magnolia, coconut, palm, sesame oil and similars. 2) mono-, di- e triglycends, semisynthetic and synthetic: containing saturated and/or unsaturated fatty acids (with aliphatic chains length variable between C 6 and C 22 ), their poly-hydroxyethyl derivatives.
• capricocaprylic triglycerids (MygliolTM , CaptexTM, LabrafacTM Lipo), polihydroxylated triglycerids of different kind, saturated or unsaturated (LabrafilTM, LabrafacTM Hydro, GelucireTM).
• "liquid waxes” isopropyl miristate, isopropyl-caprinate, -caprilate, -laurate, - palmitate, -stearate; fatty acid esters, such as ethyl oleate, oleyl oleate.
• aliphatic and aromatic alcohols hexadecyl alcohol, oleic alcohol, lauric alcohol, cetylstearyl alcohol, benzyl alcohol and their poly-hydroxyethyiated derivatives.
• aliphatic carboxylic acids preferably with short or middle (C 4 -C 10 ) chain, like decanoic acid, butanoic acid, etc., and their poly-hydroxyethyl derivatives.
• a preferred composition according to the invention can contain, as oily dispersed phase (I) a mixture of LabrafacTM Hydro (PEG 4 glyceryl caprilate- caprate) and benzyl alcohol, witb relative ratios between 100 and 0,01.
• oily dispersed phase (I) a mixture of LabrafacTM Hydro (PEG 4 glyceryl caprilate- caprate) and benzyl alcohol, witb relative ratios between 100 and 0,01.
• hydrophylic carriers according to the invention are natural products, synthetic or semi-synthetic products, which can be defined as aqueous carriers not mixable or only partially mixable with oil. All components can be used alone or if possible in mixtures with different percentages.
• aqueous components which can be used preferably as dispersing phase (II), but also as dispersed phase (I), we can mention:
• hydrophilic polymers which are hydrosoluble or hydrodispersable of various nature, like polyethylenglycol, polyvinylpyrrolidone, polyacrylic acids and derivatives (for example CarbopolTM, PremulenTM, ecc), polymethacrylic acids and derivatives (for example EudragitTM), polyoxyethylene- polyoxypropilene copolymers (for example Poloxamer, LutrolTM), polysaccharides of various nature, for example dextran, xanthan, scleroglucan, arabic gum, guar gum, chitosan, cellulose and starch derivatives.
• hydrophilic polymers which are hydrosoluble or hydrodispersable of various nature, like polyethylenglycol, polyvinylpyrrolidone, polyacrylic acids and derivatives (for example CarbopolTM, PremulenTM, ecc), polymethacrylic acids and derivatives (for example EudragitTM), polyoxyethylene- polyoxypropilene copolymers (
• polyethylenglycols for example PEG 200, PEG 400, PEG 600, PEG 1000
• polyglycolic glycerides for example LabrasolTM.
• polyglycols like for example propylene glycol, tetraglycol, ethoxydiglycol (TranscutolTM).
• a preferred composition according to the invention can include as dispersing aqueous phase (II) a solution of LutrolTM 127 in water, at a concentrations in the range 1% and 50%.
• aqueous phase II
• surfactant (III) and cosur actant (IV) in different ratios depending on the nature and type of the components is of paramount relevance in order to form the biphasic system in accordance to the invention.
• non- ionic surfactants with HLB value higher than 7 , like for example: sorbitane esters of fatty acids (Tween, Capmul * ,Liposorb' ), polypropylenoxide-polyethyleneoxide copolymers (Poloxamer), polyethyleneglycol esters (PEG-glycerol, Labrasol, Labrafil with HLB 6-7), PEG esters and long-chain aliphatic acids or alcohols (Cremophor), polyglyceryl esters (Plurol), esters of saccharides and fatty acids (sucroesters).
• sorbitane esters of fatty acids Teween, Capmul * ,Liposorb'
• Polypropylenoxide-polyethyleneoxide copolymers Polypropylenoxide-polyethyleneoxide copolymers
• Polyethyleneglycol esters PEG-glycerol, Labrasol, Labrafil with HLB 6-7
• anionic surfactants can be used (e.g., sodium laurylsulphate, sodium stearate, sodium oleate ) or cationic (e.g., tricetol ), as well as lecithins, phospholipids and their semi-synthetic or synthetic derivatives.
• cosurfactants (IV) we mention short-chain alcohols, e.g. ethanol, 2- propanol, n-butanol, isopropanol; aliphatic acids (e,g. butirric acid, valerianic, capronic acid) with short or middle chain length; aromatic alcohols such as benzyl alcohol.
• Middle-chain aliphatic alcohols and acids C 8 - C 12
• acids such as decanoic acid, lauric acid, caprinyl alcohol, lauryl alcohol.
• cosurfactants are esters or ethers of aliphatic, middle-long-chain acids or alcohols with mono or polyhydroxyl alcohols. Some of the mentioned cosurfactants can be at the same time constituents of the oily phase of the microemulsion.
• a preferred composition according to the invention includes: as an oily dispersed internal phase (I), a mixture of Labrafac Hydro (PEG-4 glyceryl 10
• aqueous dispersing phase (II) a Lutrol 127 solution in water, with concentrations in the range 1 %-50%, and a surfactant (III), Tween 80 , in the concentration range comprised between 5% - 15% by volume.
• phase (I) benzyl alcohol
• cosurfactant (IV) one of the components of the phase (I) (benzyl alcohol) acts also as cosurfactant (IV).
• Essential components of this invention are the compounds (VI) , which are able to modify unexpectedly the oil/water partition coefficient of the drug in the system.
• compounds (VI) are generally, though not necessarily, amphiphylic and non-ionic.
• the modification of the partition of the drug depends on the type and concentration of compound (VI): consequently the active principle may enrich either phase, with consequent influx on the percutaneous absorption rate. This result can be obtained without changing the composition according to the invention in its constituents (l-V).
• NMP N- methyl pyrrolidone
• DPPG propylene glycol dipelargonate
• betacylodextrin hydroxypropyl beta- cyclodextrin, and dimethyl beta-cyclodextrin.
• some compounds ( VI ) can form specific complexes with some drugs, directly affecting the concentration in the phases of the biphasic system, and the transdermal permeation of the drugs.
• N-methyl-pyrrolidone is particularly interesting ; for example a preferred composition according to the invention includes: Labrafac Hydro (PEG-4 glyceryl caprylate-caprate) and benzyl alcohol with relative ratios within the range 10:1 - 1 :1 (and with concentration comprised between 5% and 15% v/v); water ( from 45 % to 60 % in volume ), Lutrol 127 (5-15%),Tween 80, in a percentage between 5 and 20 % by volume, and NMP in volumetric concentrations in the range 3% - 20 %.
• the composition of the invention can typically include: 1. One or more lipophilic or oily carriers with percentages in the range 0,5% - 80%, preferably 5%-40% by weight.
• One or more aqueous components in the weight range of 0.5% - 75%, preferably 35%-70% by weight. 11
• Surfactants ( III ) ionic or non-ionic, in the range 0.1 %-50% , preferably 1 %-
• a specific surfactant cosurfactant ratio > 1.
• One or more drugs preferably in the range 0.1 %-60%, if dissolved in the system; 0.1 %-25% if the drug is dispersed.
• compositions of the invention can contain suspending agents, gelling agents, viscosity enhancers.
• colloidal gelling agents such as silica gels (Aerosil ®) in the concentration range 1 %-15%, preferably 3%-10%.
• polymeric gelling agents can be used: examples are the polyacrylic acid derivatives ( Carbopol , Noveon , Pemulen ) polymethacrylate (Eudragit ®), both in the range 0.1 - 10%; polyethylene oxide - polypropylene oxide copolymers (e.g. Lutrol®), usually between 2.5% and 30%; polyvinilpyrrolidone (e.g.
• any substance capable of forming gels in presence of various amounts of water or other solvents can be used for the purpose of the invention.
• the preparation process is generally performed by initially mixing the lipophilic or oily carrier, the cosurfactant, and a fraction of the surfactant necessary for the formulation, variable between 0% and 75% of the calculated total; this system is kept under mild stirring in a mixer or in an emulsifier.
• the preparation temperature and the thermal stability range may vary depending on the components; usually the temperature is in the range of 5°-85°C, preferably 15°-45°C.
• the water phase is added to the other components in the reactor, usually at room temperature, under moderate stirring temperature control. Once the two phases are mixed, the remaining part of the surfactant is added, allowing the formation of 12
• the compound VI "partitioning modifier" is usually added to one of the phases before mixing, depending on its mixability with the aqueous or oily phase.
• the quantity and concentration of the drug depends on the therapeutical purpose of the composition; the method of adding the drug depends on its physico- chemical properties.
• the drug is added to the already formed composition, being soluble in one or both phases of the system; so both hydrophilic (e,g. diclofenac sodium) and lipophilic drugs (e,g. progesterone) can be added to the system.
• the solubility of the drug in the composition is advantageously higher than in the single separated phases.
• compositions according to the invention require minor percentages of surfactacts (III), when a drug or a partitioning modifyer-drug complex with surfactant action is present in the above composition. In such cases the drug results to be not only a solute but also an essential component of the composition.
• the multicomponents systems of the invention can be further formulated as the pharmaceutical dosage forms known in the art for topical or systemic administration of drugs.
• compositions can be introduced in gel formulations, as above described, using known processes, as the addition of gelling polymers under mixing and vacuum in order to avoid the formation of air bubbles.
• the gel matrix can be directly applied to the skin or to be included in a transdermal application device such as the Hilltop® chamber.
• the multicomponent composition can also be included, as liquid, viscous liquid or gel, in a transdermal system, e.g. a reservoir system consisting of a device and a diffusion membrane, and "drug-in-adhesive" system directly on the skin, similarly 13
• composition suitable for topic administration can be formulated in gel directly applicable
• compostions for oral or transmucosal use can be formulated in liquid capsule, soft-gel capsules, suppositories and applicators normally used in the administration of aqueous or oil liquids.
• compositions according to the present invention can increase the skin and transdermal permeation rate of the active principles without the necessity of modify the composition of the multicomponent biphasic system in its essential elements (defined as components I -IV).
• This unexpected characteristic is realizable thanks to the presence in the formulation, in the aqueous and oil phase, of particular compounds, generally but not necessarily of amphiphilic kind, able of modifying the partioning coefficient of the active principle between the oil (lipophilic) and water (hydrophilic) component.
• the method of preparation consists in mixing the oil, the cosurfactant and part of the surfactant; further mixing the water phase containing the component (VI), "partition modifier”; adding the remaining surfactant until the system is transparent and the active principle is dissolved or suspended.
• VI component
• NMP N-methyipyrrolidone
• composition II A composition is prepared, corresponding to composition I, where the "partition modifier” NMP accounts for 10.75% by weight, and the water content is increased to 49.74% by weight.
• Composition III A composition is prepared, corresponding to composition I, where the "partition modifier” NMP accounts for 6.25% by weight, and the water content is increased to 52.24% by weight.
• Composition IV A composition is prepared, corresponding to composition I, where the "partition modifier” NMP accounts for 6.25% by weight, and the water content is increased to 52.24% by weight.
• composition is prepared, corresponding to composition I, where the "partition modifier" NMP accounts for 3.25% by weight, and the water content is increased to 52.24% by weight. 15
• composition III A composition is prepared, corresponding to composition III, where the "partition modifier” NMP accounts for 6.25% by weight, and the active principle is sodium diclofenac (3.50% by weight)
• composition V A composition is prepared, corresponding to composition V, where the active principle is sodium diclofenac (3.50% by weight), and the "partition modifier" NMP accounts for 3.25% by weight.
• composition is prepared, corresponding to composition VIII, where the "partition modifier” propylene glycol accounts for 6.35% by weight, and the water content is
• composition is prepared, corresponding to composition VIII, where the "partition modifier” propylene glycol accounts for 6.35% by weight, and the water content is
• composition XII A composition is prepared, corresponding to composition VIII, where the "partition modifier" propylene glycol accounts for 15.85% by weight, and the water content is 45.85% by weight.
• Composition XII A composition is prepared, corresponding to composition VIII, where the "partition modifier" propylene glycol accounts for 15.85% by weight, and the water content is 45.85% by weight.
• the active principle papaverine hydrochloride is thus added and dissolved at a concentration of 20mg/ml of composition.
• composition XIV A composition is prepared, corresponding to composition XII, where the "partition modifier" NMP accounts for 12.5% by weight, and the active principle is verapamil hydrochloride, at a concentration of 20 mg/ml.
• Composition XIV A composition is prepared, corresponding to composition XII, where the "partition modifier" NMP accounts for 12.5% by weight, and the active principle is verapamil hydrochloride, at a concentration of 20 mg/ml.
• composition XV The active principle nimesulide is thus added and dissolved at a concentration of 3 mg/ml of composition.
• Composition XV Composition XV
• composition XIV A composition is prepared, corresponding to composition XIV, where the "partition modifier" NMP accounts for 12.0% by weight, and the active principle is estradiol at a concentration of 2.5, 5 or 10 mg/ml.
• the water content is 48.9% by weight.
• Composition XVI The following composition is prepared:
• the composition contains a part of the active principle in dissolved form, and another part as a micronised suspension homogenously dispersed within the semi-transparent system, in order to reach 5% by weight.
• Pemulen TR-1 is added to the composition after dissolving/dispersing the active principle into the other components.
• the method of preparation consists in mixing the oil, the co-surfactant and part of the surfactant; further mixing the water phase containing the component (VI), "partition modifier”; adding the remaining surfactant until the system is transparent and the active principle is dissolved or suspended.
• the gelling material is added under stirring to the composition, in order to disperse / dissolve it uniformly into the composition.
• the gelling polymers or colloids may be added in a reactor under vacuum, in order to prevent the formation of air bubbles.
• NMP N-methylpyrrolidone
• DIEP Diclofenac hydroxyethyl pyrrolidine
• Carbopol ® 940 P An amount of polyacrylic acid Carbopol ® 940 P is added under stirring and at room temperature to the thus prepared composition, in order to turn the composition into a stable and transparent gel .
• the percentage of Carbopol 940P was found to be 3.18% by weight.
• NMP N-methylpyrrolidone
• composition corresponding to composition XVII is prepared, where the "partition modifier" NMP accounts for 10.62% by weight , the active principle is DIEP at a concentration of 3.58% by weight, and the gelling agent is Pemulen TR-1 at 3.19%.
• composition XXI A gelled composition is prepared according to the present invention, being made of:
• Lutrol F127 10.50 % by weight
• DIEP (diclofenac hydroxyethyl pyrrolidine) 3.52 % by weight
• Carbopol 940P 3.27 % by weight
• the preparation is started by dissolving Lutrol F127 in water, in presence of NMP and triethanolamine, under stirring at 5°C. Thereafter the oil components (Labrafac, benzyl alcohol) and the surfactant are added to the aqueous phase, while the temperature of the reaction vessel is raised to 25°C. The DIEP is dissolved into the transparent system, and the multi-component system is then gelled by adding the gelling polymer Carbopol 940P.
• EXAMPLE 3 Composition XXII
• composition is prepared: Water 48.10 % by weight Benzyl alcohol 8.03 % by weight
• NMP N-methylpyrrolidone
• Diclofenac hydroxyethyl pyrrolidine(DIEP) 3.50 % by weight
• composition in thus formulated into a transdermal system ("reservoir” type) consisting of a diffusional membrane selected among those commercially available (3M type 10A/AA), and a polymer envelope containing the composition itself.
• a transdermal system consisting of a diffusional membrane selected among those commercially available (3M type 10A/AA), and a polymer envelope containing the composition itself.
• composition corresponding to composition XIX is prepared, where the "partition modifier" NMP accounts for 10.98% by weight , the active principle is DIEP at a concentration of 3.5% by weight, and the gelled matrix is loaded on a matrix support available on the market (e.g. Hilltop ® Chamber), supported by an external adhesive layer.
• the "partition modifier” NMP accounts for 10.98% by weight
• the active principle is DIEP at a concentration of 3.5% by weight
• the gelled matrix is loaded on a matrix support available on the market (e.g. Hilltop ® Chamber), supported by an external adhesive layer.
• EXAMPLE 4 Effect of the "partition modifier" on the partition of the active principles among the oil components of the system
• the apparent partition coefficient (P for some active principles, among the oil and water phases of compositions according to the invention, is reported for example purpose.
• the results show that, in presence of "partition modifiers" according to the present invention (component VI), the active principle is distributed, in a surprising manner, towards one or the other phases of the composition.
• Measured amounts of the oil component (Labrafac Hydro, Benzyl alcohol 1 :1 ) were contacted, under stirring for 24 hours, with equal volumes of water components (Acqua) containing different percentages of some "partition modifiers” (NMP, propylene glycol-PG, Transcutol-TC, Isopropanol-IPOA) .
• the water volume contained a starting concentration of active principle (C 0 ) which was lower than the solubility of the active principle in each of the two phases.
• C 0 concentration of active principle
• concentrations of active principle in the water phase were measured by cromatography (HPLC) .
• the apparent partition coefficient P m was calculated according to the following formula:
• Table 1 apparent partition coefficient (P for some active principles, among the oil and water phases of compositions according to the invention.
• Oily phase Labrafac Hydro
• benzyl alcohol 1 1
• Aqueous phase Water
• partition modifier 22
• DIEP Diclofenac hydroxyethyl pyrrolidine
• DIEP DIEP - N-methylpyrrolidone
• NMP N-methylpyrrolidone
• FIG. 1 shows the phase diagrams in aqueous solution of diclofenac hydroxyethylpyrrolidine salt
• figure 3 shows the phase diagrams in aqueous solution of acyclovir (ACY) and N- methylpyrrolidone (NMP).
• ACY acyclovir
• NMP N- methylpyrrolidone
• compositions containing the same excipients were prepared, only differing in the presence (or absence) of the "partition modifiers".
• the comparative data are reported in figures 5-9.
• Comparative composition A (compared with composition I , example 1 )
• DIEP Diclofenac hydroxyethyl pyrrolidine
• Comparative composition B (compared with composition V , example 1 ) Water 60.70% by weight
• Comparative composition C (compared with composition XII , example 1 ) Water 49.7 % by weight
• Comparative composition D (compared with composition XIV , example 1 ) Water 60.9 % by weight
• Nimesulide 3 mg/mL of formulation Comparative composition E (compared with composition XVI , example 1 ) Water 47.7 % by weight
• compositions according to the invention and the reference compositions were introduced in the donor compartment of the Franz cells, at constant and defined volumes/ amounts (generally 2.5-3 ml, or 2.5-3 g).
• the acceptor compartment contained saline solution and phosphate buffer, pH 7.4; the skin samples were interposed between the two compartments, and the temperature was kept constant at 37°C for the whole duration of the experiment.
• samples were taken from the acceptor phases, and the content was analysed by chromatograpy (HPLC). The results were reported as transdermal permeation curves, whose linear tract allowed to extrapolate the flux values or transdermal permeation rate, to be defined as:
• compositions according to the invention containing some of the active principles and "partition modifiers" as mentioned above; we also report their comparison with the reference compositions.
• DIEP diclofenac hydroxyethyl pyrrolidine
• composition I (figure 5); sodium diclofenac, composition V (figure 6); papaverine hydrochloride, composition XII (figure 7); nimesulide, composition XIV (figure 8); acyclovir, composition XIV (figure 9).
• figure 5 shows the transdermal permeation of diclofenac hydroxyethylpyrrolidine in the composition I of example 1 (curve (A)), compared with the composition A, of example 7 (curve (B));
• Figure 6 shows the transdermal permeation of sodium diclofenac in the composition V of example 1 (curve (A)), compared with the composition B of example 7 (curve (B));
• Figure 7 shows the transdermal permeation of papaverine. HCI in the composition
• Figure 8 shows the transdermal permeation of nimesulide according to the composition XIV of example 1 (curve (A)), compared with the composition D of example 7 (curve (B));
• Figure 9 shows the transdermal permeation of acyclovir according to the composition XIV of example 1 (curve (A)), compared with the composition E of example 7 (curve (B)).
• Figure 10 shows the transdermal permeation rate (flux) and the partition coefficient (PJ of diclofenac hydroxyethylpyrrolidine (DIEP) relevant to the compositions 1,11, II, IV of example 1 containing the partition modifier N-methylpyrrolidone (NMP) , in comparison with the composition (A) lacking NMP.
• Flux transdermal permeation rate
• DIEP partition coefficient
• NMP partition modifier N-methylpyrrolidone
• Figure 11 shows the transdermal permeation rate (flux) and the partition coefficient (PJ of DIEP relevant to the compositions VII, IX, X, XI of example 1 containing the partition modifier propylene glycol (PG), in comparison with the composition (A) lacking PG.
• Biphasic multicomponent pharmaceutical composition consisting of an oil phase and a water phase comprising:
• ⁇ one or more lipophilic or oil carrier ⁇ one or more hydrophilic or aqueous carrier;
• one or more active principle for pharmaceutical use characterized by furtheriy comprising a compound able to modify the partition of the active principle between said phases, and optionally one or more compounds with a gelling action.
• Composition according to claim 1 characterized by comprising from 0.5 to 80% by weight of said lipophilic or oil carrier, from 0.5 to 75% by weight of said hydrophilic or aqueous carrier, from 0.1 to 50% by weight of said surfactant, from 0 to 50% of said cosurfactant having a surfactant/cosurfactant rate comprised between infinity and 1 , from 0.1 to 60% by weight of said active principle and from 0.1 to 30% by weight of said compound able to modify the partition of the active principle.
• Composition according to claim 1 characterized by comprising from 5 to 40% by weight of said lipophilic or oil carrier, from 35 to 70% by weight od said hydrophilic or aqueous carrier, from 1 to 20% by weight of said surfactant, from 0 to 20% of said cosurfactant having a surfactant/cosurfactant rate comprised between infinity and 1 , from 0.1 to 25% by weight of said active principle and from 2.5 to 25% by weight of said compound able to modify the partition of the active principle.
• Composition according to claim 1 characterized by the fact that compound able to modify the partition of the active principle is selected from the group consisting of N-methyl pyrrolidone (NMP), isopropyl alcohol, propylene glycol, ethoxy-di-glycol, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin and dimethyl ⁇ - cyclodextrin.
• NMP N-methyl pyrrolidone
• isopropyl alcohol propylene glycol
• ethoxy-di-glycol propylene glycol
• ⁇ -cyclodextrin hydroxypropyl ⁇ -cyclodextrin
• dimethyl ⁇ - cyclodextrin dimethyl ⁇ - cyclodextrin.
• composition according to claim 1 characterized by the fact that said compound able to modify the partition of the active principle is an amphiphilic compound.

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• 1997
  • 1997-05-13 IT IT97MI001115A patent/IT1291362B1/it active IP Right Grant
• 1998
  • 1998-05-13 ES ES98929313T patent/ES2213908T3/es not_active Expired - Lifetime
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