Title of Invention

A NOVEL INTER AND INTRA MULTILAMELLAR VESICULAR COMPOSITION

Abstract

The present invention is related to the development of a novel inter and intra multilamellar vesicular composition containing an antipsoriatic drug dithranol. The exquisitely structured mesophase made up of saturated phospholipids (which have an inherent antioxidant property and protect the lipid soluble molecules) at the micro range level improve the overall performance of the drug by way of modifying and controlling the release as well as the reactivity of the drug. Further, such microstructured system in conjunction with hydrocolloid gel makes the system Theologically more acceptable. Thus, the formulation so developed tends to make the drug molecules effective at a reduced dose level, non-irritant, non-staining, easily applicable (stays on the affected site) and stable as well. Besides this, there is an added advantage allowing an enhanced application time vis-a-vis the short contact therapy presently practiced. Also, the formulation developed has the potential to incorporate an increased dose level of the drug without any irritancy and staining where the severity of disease demands so. Thus, the product has improved the dithranol therapy along with some additive advantageous features.

Full Text

A novel inter and intra multilamellar vesicular composition Field of Invention: This invention relates to the field of drug delivery wherein the drug molecules are accommodated at various levels within the system (encapsulated or non-encapsulated) so that their transport to the target site is effected in a most desirable manner The delivery system is structured by selecting the appropriate components of varied physico-chemical nature and designing them in an architectural pattern which suits for the purpose This invention is for dermal problems like psoriasis where the delivery of the drug dithranol is desired at the epidermal germinal layer by way of generating microstructures m-situ with the help of bio-friendly and most suitable components Background of invention: Dithranol is the drug of choice for the topical treatment of psoriasis and many other skin afflictions The drug is preferred over other therapeutic options in psoriasis like corticosteroids because of prolonged remission obtained with dithranol (relapse rate is very low) whilst the corticosteroids are associated with many serious side effects at local and systemic level 1 e rapid recurrences, skin atrophy and generalized immuno-suppression It is the drug of choice in stable plaque psoriasis, which is the most prevalent form of psoriasis It is also used in many other skin afflictions such as chronic eczemas, dermatophytoses, alopecia areata, and seborrheic dermatitis etc But at the same time, the dithranol molecule is not patient friendly because of high irritation, staining of skin and clothes and penlesional inflammation These drawbacks are associated with the inherent chemical and physicochemical characteristics of the drug 1 e chemical reactivity leading to degradation (1 e auto-oxidation chain reaction resulting in formation of free radicals and oxidized products), unbalanced solubility (1 e insoluble in water and highly soluble in organic solvent) and improper partitioning and permeability And, so far made efforts to tackle these problems by way of chemical modification of the molecule or vehicular modification by using the conventional formulation approach (use of additives and oily base or creams) have met with a little success Dithranol has a long historical record of being the oldest and most efficacious topical drugs in the treatment of psoriasis (Squire, 1877, Shroot et al, 1981) It traces its ongin m the yellowish powder extract derived from a legume tree, Andira araroba that was used by aborigines of Brazil for the treatment of mycoses of the skin The active principle was found to be chrysarobin It was exported from Brazil to Goa in India, where it got the name Goa powder, which was found to have a good therapeutic effect in psoriasis (reported by Squire in 1877) During World War I, the trade with Brazil was disrupted and supply of chrysarobin was scarce This scarcity eventually led to the development of synthetic version of the drug (synthesized from purgative compound Isitizin, 1,8-dihydroxy anthraquinone) The chemical factory Bayer developed a synthetic substitute of chrysarobin, l,8-dihydroxy-9-anthrone, which was named Cignolm Cignohn was later called Anthralm in United States and dithranol in Europe In 1916, Eugen Galewsky introduced dithranol as a drug for the treatment of psoriasis Dithranol profile Chemical name 1,8-dihydroxyanthrone Empirical formula C14H10O3 Structural formula (Structure Removed) CAS registry number 1143-38-0 Molecular weight 226 23 Description yellow to orange yellow or yellowish brown, odorless or almost odorless crystalline powder Melting point 178-181°C Solubility Practically insoluble in water, slightly soluble in alcohol, ether, glacial acetic acid, sparingly soluble in acetone, soluble in methylene chloride, chloroform, dissolves in dilute solution of alkali hydroxides Pharmacokinetics and pharmacodynamics (Muller 1996, Reichert et al., 1985, Shroot et al., 1992): Topically, dithranol penetrates into the skin with an impaired stratum corneum barrier in 30 minutes and the highest concentration of unchanged dithranol is found in the homy layer But in certain forms of psoriasis dithranol finds difficulty to penetrate and so salicylic acid is incorporated as a keratolytic agent (for improved penetration) Dithranol is known to exert its antipsonatic activity by virtue of more than one modes of action It acts at various cellular, intracellular and intercellular levels, which includes nucleic acids, various biochemical pathways, and immune-mediated reactions etc to bring about therapeutic efficacy It inhibits keratmocyte proliferation and results in normalization of keratin expression Epidermal cell turnover rate is decreased by dithranol resulting in alleviation of the symptoms of the disease It also has a potent effect on cellular respiration Target organelle for dithranol is mitochondna where it accumulates and inhibits cellular respiration by its interaction with the electron transport chain, resulting finally in a reduction of ATP synthesis The lowenng of cellular energy supply results in inhibition of energy dependent process such as DNA replication which slows down excessive cell division as seen in psonasis Dithranol mechanism of action and its chemical reactivity (Goranson 1987, Mustakallio 1984, Shroot et al., 1992): A keynote of the chemical behavior of dithranol is its redox chemistry, an understanding of which highlights the nsks and benefits of this drug Chemical reactivity of the hydroxyanthrone moiety can be attnbuted to a) phenolic hydroxyl groups at C1 and C8 b) two reactive hydrogen atoms at C10 It is observed that dunng auto-oxidation process, keto-enol tautomensm of dithranol is altered resulting in the formation of 1,8-dihydroxyanthraquinone (danthrone) and 1,8,1',8'-tetrahydroxydianthrone(dianthrone) via the anthronyl radical The chemical degradative pathways (or the pathways for anti-psonatic activity) have been depicted in the following figure (Figure Removed) Oxidation of dithranol is both pH and light dependent Dithranol displays a distinct chemical behavior involving hydrogen atom abstraction and electron transfer to yield the corresponding anthronyl radical It is this chemical reaction (1 e auto-oxidation), which leads to interference with cellular metabolism that accounts for the ubiquitous pharmacology of dithranol wherein it acts as an electron donor and inhibits the electron transport chain Further, the oxidation chain leads to the formation of uncharactenzed products known as 'anthralin brown' or 'dithranol brown' that are responsible for the violet-brown staining of skin and clothes All these oxidation products of dithranol (1 e danthrone, dianthrone and dithranol brown) do not possess antipsonatic activity and are responsible for the major side effects associated with dithranol therapy Thus, it is a paradoxical situation wherein the chemical reactivity of dithranol is necessary for its antipsonatic action as an electron generating process, while at the same time it is undesirable as it leads to the formation of oxidized products that are irritating and staining Problems of dithranol, past efforts and reasons for failure (Brandt, Mustakallio, 1983; Loffler et al., 1999, Mustakallio, 1979;, Misch et al., 1981; Paramsothy, Lawrence, 1987) The problems associated with the dithranol therapy are manifold and are described as below • Irritation - The dithranol molecule gets quickly oxidized thus yielding free radicals, which damage the biological tissues and irritate profoundly It is the healthy naive tissues, which get in contact with dithranol are more irritated than the affected ones • Staining of skin and clothes - Dithranol causes staining of skin surrounding the lesions, hair and fingernails It may spoil clothing, linen and bathtubs by permanent staining Staining is due to destabihzation of dithranol molecules, which results in dark brown red color These oxidized compounds get strongly adsorbed onto the fabric of clothes and are deeply bound to skin tissues Therefore, the clothes are very difficult to wash and skin remains stained for very long time This can be ascribed to the physicochemical nature of the decomposed product • Perilesional inflammation - Inflammatory response to dithranol could be due to an oxidation metabolite Further, it is also speculated that production of free radicals by dithranol may cause specific peroxidation of arachidomc acid responsible for the inflammation of skin And, the vehicles so far used are not able to control the contact between the healthy tissues and decomposition products of dithranol • Itching, stinging, burning and dryness of the skin. • Folliculitis and contact allergy have also been reported All these undesirable effects observed dunng dithranol therapy limits the use of drug and also affect the patient compliance Therefore, in the past a lot of efforts have been made in different directions to help manage the dithranol therapy These include, majorly at the level of • Molecule modification I e chemical change in the molecule to help obtain a stable molecule But this chemical denvatisation is so far not successful as dithranol is still the most efficacious molecule amongst all of its congeners • Modification in the vehicular composition by conventional formulation approach and the addition of salicylic acid to help manage stability, solubility and spreadibihty • Modification in the treatment modality (a) By limiting the time of application (1 e short contact therapy) and limiting the dose levels (b) By applying occlusive covering (plastic film) to help penetrate the molecule The above mentioned efforts to improve upon the dithranol molecule per se as well as its formulations may be cited as below Dithranol and related hydroxyanthrones chysarobin, tnacetyldithranol and 10-butyryldithranol (butantrone) have been compared wherein the modified molecules, namely butantrone and tnacetyldithranol have shown reduced irritancy and staining while at the same time their efficacy is simultaneously compromised Mustakalho, K , K "The history of dithranol and related hydroxyanthrones, their efficacy, side effects, and different regimens employed in the treatment of psoriasis" Acta Derm Venereol 1992, Suppl 172 7-9 Various cream formulations of dithranol alone, along with salicylic acid and different stabilizers have been designed with a view to improve stability and efficacy, Kneczke, M , Rahm, C , Landersjo, L and Lundgren, P "In vitro release of anthrahn from white petrolatum and an o/w cream" Acta Pharm Nord 1989, 1, 249-258 Kneczke, M , Rahm, C , Landersjo, L and Lundgren, P "The influence of salicylic acid on the in vitro release of anthrahn from an o/w cream" Acta Pharm Nord 1990, 2, 313-18 Pnns, M, Swinkels, O Q J , Kolkman, E G W , Wuis, E W , Hekster, Y A and Van Der Valk, PGM "Skin irritation by dithranol cream A blind study to assess the role of cream formulation" Acta Derm Venereol 1998 (Stockh), 78, 262-65 Dithranol has been encapsulated in a matrix of semicrystalhne monoglycendes and marketed under the tradename Micanol® Lindahl, A "Embedding of dithranol in lipid crystals" Acta Derm Venereol 1992, Suppl 172 13-16 Mixed vesicular system containing a nanoemulsion with bilayer nanovesicles mimicking niosomes and liposomes (of size 450nm) for topical delivery of dithranol, Gidwani, Suresh Kumar et al, Composition for delivery of dithranol, US patent application 20030219465 Dithranol (0 5%) has been incorporated in commercially available liposomal gel Natipide® II and liposomes of size 220nm have been obtained In this study the penetration of dithranol in the skin has been reported to increase (which is a measure of increased erythema or redness of the skin) with a 10 minute occlusive application of the liposomal gel The enhanced erythema, after liposomal application, however is unwanted as it may lead to irritancy alongside Gehnng, W , Ghyczy, M , Gloor, M , Scheer, T and Roding, J "Enhancement of the penetration of dithranol and increase of effect of dithranol on the skin by liposomes" Arzneim-Forsch 1992, 42(7), 983-985 Pharmaceutical preparation containing dithranol have been prepared in a earner which contains 40 to 60% of liquid paraffin, 40 to 60% of solid paraffin, and 0 5 to 5% of microcrystalhne wax, the composition can be designed into thin, hard and non-brittle sticks for precise application to the site, Mustakalho, et al, US patent no 4699929 Dithranol polyvinylpyrrolidone (Di PVP) coevaporates have been prepared to increase the aqueous dispersibihty of dithranol , these coevaporates contained small crystals as well as nanoparticles of dithranol embedded in the PVP matrix Delneuville,I, Dechesne,J P and Delattre,L "Preparation and study of the charactenstics of dithranol polyvmypyrrohdone coevaporates" Int J Pharm , 168, 109-118 Pharmaceutical composition compnsing oil in water emulsion containing dithranol and nonionic vesicles prepared from nonionic amphiphihc lipids, in order to prevent the oxidation of dithranol The vesicles are dispersed in aqueous phase of the emulsion and dithranol is not encapsulated in the vesicles, Laugier, Jean Pierre et al, Pharmaceutical composition for topical application containing dithranol and preparation process, US patent no 5358716 A composition containing dithranol, an acid and anti-oxidant, petroleum jelly, which may be mixed with a spreadable synthetic rubber, water, and an emulsifier This composition shows a reduced staining and little tendency to spread, Yarrow, et al, USpatent no 4203969 A liquid preparation of film forming polymers and dithranol, with which the psoriasis affected site can be covered and treated in situ with a medicated film or foil formed at the treatment site, Mueller, et al, US patent no 4826677 An anhydrous composition containing dithranol in a pharmaceutically acceptable anhydrous vehicle (formulated from glyceryl monostearate and isopropyl mynstate or isopropyl palmitate), Stable dithranol compositions in anhydrous vehicles, Van Scott et al, US patent no 4367224 Pharmaceutical compositions for topical application to the skin containing a dissolved, emulsified or suspended active ingredient (triamcinolone, dithranol, urea or mixture of these) encapsulated in liposomes The compositions are formulated as ointments or creams, Muller Josef, Topical pharmaceutical compositions, Patent no ES2002917 Summary of the invention: In the present invention, it has been identified that stabilization is not the sole factor needed for improvement It has been discussed earlier that dithranol acts as an electron donor and blocks the electron transport chain in mitochondna of affected cells, thereby bnnging about a halt in vanous energy dependent processes including cell division So, it can be clearly seen that electron generating capacity 1 e the oxidation of molecule is involved (which is the resultant of dithranol decomposition or instabihty)in the therapeutic action Therefore, it can be stated that chemical reactivity (oxidation) of dithranol is rather a required step for its therapeutic action However, it is known that the oxidation of dithranol results in production of oxidized products, namely, danthrone, dianthrone and anthralm brown, which are responsible for all the side effects associated with dithranol It can, therefore, be concluded that the present approach of dithranol stabilization is not altogether correct because stabilizing dithranol molecule means hindenng its chemical reactivity (1 e oxidation process) that will eventually result in lowenng down of therapeutic efficacy In the light of above paradoxical situation, the degradation of dithranol is desired (for antipsonatic activity) as well as not desired (for safety and patient compliance) The need of the hour is to moderate the process of degradation in a controlled manner by developing a suitable earner design composed of appropnate components, which will exert an appropnate (1 e as and when required) control over dithranol reactivity The earner/delivery system should keep dithranol in stable form dunng storage (1 e before application to the skm) This will prevent oxidation of dithranol and subsequently the formation of oxidized products that cause irritation and staining (and these oxidized products do not exhibit any antipsonatic activity) Secondly, after application to skin, the earner system should result in a controlled release of dithranol to the affected area, which will bnng about a sufficient reactivity (1 e auto-oxidation reaction) in order to exert a desired therapeutic action with minimum of side effects The present work was initiated, after identifying the core problems of molecule and the faults in its delivery mechanism, to help evolve some unique strategy, which would allow the drug to locate the site of action in a most wanted fashion, so that the problems of dithranol are minimized and at the same time its efficacy is well preserved or even maximized And remarkably, the earner system in its strategic design proved to be successful in bnngmg about a new potential in this age-old molecule These earner systems are basically a liquid crystalline state of the matter, better known as smectic mesophase, which are built on some bio-fnendly class II polar compounds (saturated phospholipid molecules) in conjunction with other additives which are supramolecularly arranged to provide the lipid ennched biphasic (aqueous and non-aqueous) state The drug is dispersed at the molecular level within such an inter and intra multilamellar design This formulation design is novel in the sense that it provides the desired micro-environment for the drug activity The microstructured earners help in the desired delivery of the dithranol molecule to the vanous psonatic targets at the inter and intra cellular level as the drug finds an improvised access therein that allows to accommodate dithranol molecule at the inter and intra compartmental spaces And, it provides the drug a desired physicochemical cover so that the molecules are dispersed at the molecular level in a biphasic state (1 e in the hydro-hpophihc ambience) Chemical degradation reaction that generates the free radicals is controlled in this earner system This chemical reactivity is responsible for lintant and staining effect of the drug, but at the same time it is desired for therapeutic action that blocks the electron transport chain in the psonatic cells The earner system not only makes the drug safely and effectively delivered but also makes the drug-receptor interaction at vanous levels of targets (cellular, intercellular and intracellular) as the drug molecules are encaged strategically in the entire system The earner also improves the rheological behavior (1 e thixotropy) of the formulation so that the molecules are confined to the afflicted area and do not spread to normal skin tissues surrounding the psonatic lesions The latter minimizes the irritancy and skin staining while the conventional formulations are unable to prevent the contact of dithranol with normal skin, which is the prime cause of these side effects The earner also makes the drug easily washable which otherwise gets strongly absorbed onto the fabnc and makes the clothes heavily stained (in conventional formulation) Further, there is observed a synergism in the therapeutic action by way of the formulation components as the dose is reduced significantly 1 e approximately 50% And the product does not require the incorporation of other frequently used agents like salicylic acid that are known to cause irritation, as dithranol alone is sufficiently effective on its own Thus, there is an overall improvement in the formulation on varied fronts of efficacy and safety, which is worked on the principles of improvised delivery The overall improvement in the formulation can be attnbuted to • Drug Transport Enhanced drug penetration across the tough and dense lamellar hpidic matnx of stratum corneum is achieved as a result of favorable hydro-hpophihc microenvironment built in by these micro-earner systems which keep the drug molecule encaged within their intenor This is because of the possible earner-skin lipid interaction that helps in the partitioning of the drug and facilitates the skin transport The simultaneous modification in the barner function of stratum corneum due to incorporation of phospholipids (into skin layers) also favors the transport of drug across skin • Control on release, reactivity and stability Phospholipid molecules known for the anti-oxidant activity provide a supramolecular cover to the highly unstable dithranol molecule that is placed within the system The drug molecule remains protected (this feature is responsible for improved shelf-life or storage life of the drug) but when they are applied, release at a controlled rate from the mtra-lamellar domain, and tend to auto oxidize along with the molecules that are already present at the inter-lamellar space This results in controlled oxidation and sufficient electrons are generated for the desired action on psonatic targets (so that the electron transport chain is blocked and cell division and subsequent proliferation is restneted) The rate of release of drug from intenor compartments is well controlled by way of multilamellar membrane barner So, in totality the drug molecule placed at inter and intra compartmental sites show moderation in reactivity to obtain improved safety as well as efficacy • Super-solvent effect Phospholipid-based earner systems by virtue of the amphiphilicity and supramolecular association provide a super solvent effect, which keeps the active medicament in molecularly dispersed state so that the transfer across the skm is facilitated • Prolonged and pronounced local action Increased drug-localization in the skin strata is expected by the formation of micro-reservoirs, which results in confinement and retention of drug within affected skin tissues This helps to produce prolonged local action and reduced side effects Besides prolonged presence, the pronounced action is another benefit that may be attributed to the presence of the therapeutic molecules at or near the target site The drug in the earner may produce better drug-target interactions • Dose reduction & improved therapeutic index The above mentioned points conglomerate to lead to a reduction in the dose level to almost half of the dose of conventional preparation (1 e 0 5% w/w vis-a-vis 1 15% w/w of conventional preparation) This is a substantial enhancement in the therapeutic index of the drug So, the safety of the drug is also expected to be increased, because an enhanced drug action is obtained as a lesser number of molecules are required to elicit the desired pharmacotherapeutic effect And also the hydrating effect in the lipid rich environment also reduces the irritant effect of the molecule • Skin nutrition Phospholipids earner-based product provides the desired skin moistunzing and emollient effect Phospholipid ennched system (l e multilamellar system with lamellae compnsing of phospholipid molecules vis-a-vis unilamellar systems) add value to the product as the skin is fed with the desired membranous lipids that too in a hydrated state • Improved patient compliance Reduced lrntancy and staining along with favorable rheological properties of the system in contrast to greasy ointments make it cosmetically more acceptable and improve the patient compliance • Less staining and easily washable Dithranol molecule being highly lipophilic gets deeply bound to skin tissues and the fabnc of the clothes thus making it very difficult to wash out, while dithranol micro enclosed in this system gets a lesser chance of direct interaction with skin or fabnc Also, this system being surface active in nature does not allow dithranol to be strongly bound to these surfaces, thus making it easy to wash off with warm water without any need of detergent Moreover, the aqueous gel base forms the external vehicle of the product that makes the preparation easily washable from skin as well as clothing The present invention could peep deep down into the troubles of dithranol and diagnose the desired delivery dimensions of the drugs that remained hitherto not focused properly However, few products have been made available in the market (e g Micanol) based on some entrapment strategy and could deal with some aspects of dithranol delivery but none could result into desired success which will take care of the drug in toto The present product has made success, after identifying the problem in right form and projecting the hypothesis accordingly, by entrapping the drug at the intra and inter-lamellar microstructured domains composed of most conducive molecular compositions at the supramolecular level The strategically composed systems with carrier effect could help modify the vanous chemical and physicochemical characteristics of the drug such as reactivity, release, solubility, stability and spreadibihty that in turn end up with a unique formulation which is improved on its shelf-life, efficacy, safety (non-irntating), patient compliance (non-staining on clothes and skin), rheology (thixotropic) and cosmetic value The formulation so developed is not only effective at the reduced dose level but now can bear enhanced dose level that is desired in certain types of psoriasis and also can be left in contact with the affected site for a prolonged period of time (in contrast to presently practised short contact therapy) Further, the formulation does not need any additional support such as that of salicylic acid (an irritant molecule) and occlusive plastic covering onto the affected site Detailed description of the invention: The drug along with the lipid components namely, phospholipid, cholesterol and butylated hydroxyl toluene are dissolved in sufficient amount of chloroform in a round bottom flask The flask is then attached to the rotavapor for evaporation of the solvent and formation of a thin film The flask is subjected to overnight vacuum for complete removel of the residual solvent The dry, thm film is then hydiated with phosphate buffered saline of pH 6 4 containing sodium metabisulfite The suspension so obtained is kept for separation of layers and the supernatant is removed so as to adjust the final concentration of the product The suspension is added to the required amount of methylcellulose so as to gel the entire system The addition of methylcellulose is a crucial step, wherein methylcellulose is made into slurry at high temperature (60 to 65°C) and then added to the entire system at a substantially lower temperature (0 to 5°C) This transition in temperature allows to form a gel product in a quicker succession so as to encage the vesicles within the gel matrix to help maintain the uniformity The vanous parameters which influence the quality of the product include the level of the drug, lipid, solvent, nature of the hydration medium, hydration temperature and the process variables such as rotational speed, temperature and the surface area of the glass support etc The maximum amount of drug loaded into vesicles was observed to be 3 51 mg/185 mg of total lipid for a maximum degree of entrapment for maintaining the size uniformity along with freedom from aggregation The mean size, using laser light scattering technique for dithranol vesicles was found to be 3 8±0 A\i With optical microscopy the mean size (dvn) of vesicles was found to be 3 59 + 1 5 [i The size of the vesicles is subjected to mechanical perturbations and can be varied by employing mechanisms such as vortexing and ultrasomcation However, it is initially kept at this level make the micro-earner lipid ennched system for better drug delivery The leakage of drug was recorded to be increased (≈40%) at higher temperature (37°C) While at 4°C and 25 °C vesicles have shown fairly high retention of drug, l e minimum leakage (≈ 10%) inside the vesicles up to a penod of one month (≈ 90%) A 2% methylcellulose gel with a pH maintained at 6 0±0 5 finally found suitable, the concentration of methylcellulose may vary from 1% to 5% depending on the viscosity grade The vesicles incorporated in the gel were observed to be well preserved as monitored by optical microscopy The rheological profile of the final formulation was determined and found to possess the thixotropic tendency The latter makes the product easily applicable (owing to improved spreadibihty) onto the afflicted areas but after the application does not allow it to spread to naive tissues surrounding the afflicted site, which is the main cause of lrntation and staining The final composition after addition of secondary vehicle, methylcellulose (2%), contains 0 5% w/w dithranol which includes 70 2% mtravesicular drug and 29 8% intervesicular drug The gelling agent, methylcellulose is a hydrocolloid which can be replaced by other such gel forming agents e g hydroxypropylmethylcellulose, carbopol, hydroxyethylcellulose, sodium carboxymethylcellulose, gelatin etc The vesicular systems are release rate retarding by virtue of their lamellar barner effect The release of dithranol is retarded upto 9 4fag/cm2/h from intra-lamellar spaces of the vesicles whilst in case of solution it was at much higher level of release rate 42 9 µg/cm2/h This implies that the release retarding nature of the system is helpful in controlling the activity of the drug onto the site(s) of action Also, this retarding nature helps in obtaining the depot effect so as to prolong the action of drug which can be seen in the following observation The skin retention with the formulation was observed to be 0 45 mg/4 15cm2 skm area, while in case of solution it was only 0 058 mg /4 15cm2 skin area The vesicular preparation could protect the dithranol to the extent of 91 87% in the storage conditions, 40°C/75% RH with light for a 3-month period while the conventional cream could protect up to 73 24% In the stabilization, the type of phospholipid used played a major role while the antioxidant and preservative gave a support The presence of a large concentration of the phospholipid molecules, which are inherently anti-oxidant in nature helps to protect the drug from oxidative degradation during the storage conditions The drug is also protected by virtue of its position in the system composed of biphasic I e aqueous and non-aqueous phases where the aqueous phase is a hydrogel system and not a simple aqueous solution The highly stained clothes with commercial formulation were difficult to washout even with detergent However, the vesicular systems were free from this discolouration problem and whatever little marks they left were easily washed out This is because the hpidic bilayer prevents the direct contact of the naked drug molecule with the fabric, thereby resulting in a negligible adsorption on the cloth surface, while in the conventional formulations the drug gets highly bound to the fabric and stains it permanently The observations made during irritancy studies indicate that dithranol in vesicular product has been devoid of the skin irritancy effect The conventional and commercial cream have shown a significant skin-worsening effect to a extent that application could not be continued for a stipulated time period of study The vesicular product was compared with commercial formulation while taking plain vesicular gel (without drug) as its control The dithranol-vesicular gel formulation (0 5%) has been found to have comparable efficacy to that of commercially available dithranol cream (1 15%) At the end of study (as reflected in the total seventy score [TSS] value) the reduction in TSS by dithranol vesicular gel is noted to be slightly higher (1 6±0 2), than that of commercial cream A (1 5±0 2) but not significant The performance of vesicular gel in its drug content level of 0 5% vis a vis 1 15% of commercial cream is adjudged as enhanced On the issue of safety and acceptability of the dithranol formulation, vesicular product could perform much better than the commercial cream The level of adverse effects (irritation, penlesional erythema, burning sensation and staining of skin and clothes) was reported to be very low in comparison to commercial one Also the acceptability of the patients was of high order that make the product favorable by physician who was carrying the trial Another important difference of the intra and inter vesicular product with respect to the conventional product is that it does not require the incorporation of salicylic acid for stability or keratolytic activity Salicylic acid is a known irritant which is otherwise present in most of the conventional products But, here in this product the composition and its design strategy helps to do away with such irritants so as to make the product more patient friendly Thus, the improved clinical performance of dithranol in dithranol vesicles is concludingly held responsible for their various compositional factors and working mechanisms on and within the affected skin site Now with this finding the dithranol can be seen to gain a better potential and image so that its vesicular form can be allowed to treat sensitive skin areas like face and flexures Also, larger body surface areas (including soft tissues) may be safely treated without fear of severe irritation Inter and intra multilamellar vesicular composition of the instant invention containing dithranol, includes one or more other antipsonatic, keratolytic or lmmunoinflammatory agents Example Composition of the prepared dithranol liposomal product: (Table Removed) Brief description of the prepared product (Table Removed) We claim: 1. A novel controlled release drug delivery system having a dispersion of inter and intra multilamellar vesicular composition for the treatment of dermal problems for instance psoriasis, said system comprising a biphasic arrangement such that the outer phase comprises an aqueous hydrocolloidal gelling agent which constitutes the interlamellar phase and an inner phase which comprises multiple lipoidal vesicles constituting the intralamellar phase, such that the drug contained in the said vesicular composition disperses into both the phases in critically defined concentrations of 70-80% in the said inner phase and 20-30% in the said outer phase. 2. The drug delivery system of claim 1 wherein the said lipoidal vesicles have the composition of dithranol (0.25 to 1.0%), phospholipid (8-12%), cholesterol (3-7%), butyrated hydroxyl toluene (0.1-0.5%) and hydrocolloidal gelling agent (0.5-3%) dispersed in 0.2 molar phosphate saline buffer USP pH 6.4. 3. The drug delivery system of claim 1 wherein the average size of the said lipoidal vesicles ranges from 1-10 microns. 4. The drug delivery system of claim 1 wherein the said hydrocolloidal gelling agent is methylcellulose. 5. The drug delivery system of claim 1 wherein the drug is available to the skin cells in a reduced but continuous manner owing to diffusion from inner lipoid vesicles to the outer aqueous phase as degradation proceeds in aqueous phase. 6. The drug delivery system of claim 1 wherein dispersal of the drug in defined concentrations in the aqueous and non-aqueous phases permits controlled degradation of dithranol leading to free radical generation required for therapeutic effect. 7. The composition of claim 1 comprising a novel controlled release drug delivery system wherein said hydrocolloid gelling agent possesses thixotropic rheological character. 8. A controlled release drug delivery system for treatment dermal problems such as psoriasis as herein described with reference to the detailed description and examples.

Documents:

610-del-2005-abstract.pdf

610-del-2005-claims (20-03-2006).pdf

610-DEL-2005-Claims-(15-11-2011).pdf

610-DEL-2005-Claims-(30-03-2012).pdf

610-del-2005-claims.pdf

610-DEL-2005-Correspondence Others-(15-11-2011).pdf

610-DEL-2005-Correspondence Others-(30-03-2012).pdf

610-DEL-2005-Correspondence-Others-(18-06-2009).pdf

610-del-2005-correspondence-others.pdf

610-del-2005-description (complete).pdf

610-DEL-2005-Form-1-(15-11-2011).pdf

610-del-2005-form-1.pdf

610-DEL-2005-Form-13 (20-03-2006).pdf

610-del-2005-form-13.pdf

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610-del-2005-form-2.pdf

610-DEL-2005-Form-3-(15-11-2011).pdf

610-DEL-2005-Form-3-(18-06-2009).pdf

610-DEL-2005-Form-3-(30-03-2012).pdf

610-del-2005-form-3.pdf

610-del-2005-form-5.pdf

610-del-2005-gpa.pdf