Description: FIELD OF THE INVENTION
The present invention provides a stable topical non-aqueous gel composition. The present invention further provides a stable topical non-aqueous organogel composition which is essentially free of antioxidants and peroxide. The present invention further provides a process for the preparation of the stable topical non-aqueous organogel composition.

BACKGROUND OF THE INVENTION
Topical gels are semisolid systems in which a liquid phase is constrained within a three-dimensional polymeric matrix of natural or synthetic gum in which a high degree of physical or chemical cross-linking has been established. Topical gels present the ideal candidate for a variety of applications due to their intermediate behavior between solid and liquid materials. Topical gels or formulations have many advantages as compared to other conventional dosage forms. Topical gels are less toxic and more effective than other dosage forms. Topical gels are the best choice for treating local infections and skin problems because it directly applies to the skin or on the site. Topical gels provide action direct to the site of application. Topical gels exclude the GI irritation and metabolism of the drug by which the bioavailability of the drug is greater. Drug-drug interaction and food-drug interaction are also not possible in the case of topical gels. Gels have better penetrating power because gel consists of two phases. In topical applications, the total quantity of active ingredients absorbed varies greatly based on many factors including application area size, the frequency, vigor of application, and the viscosity or thickness of the applied vehicle. Other factors influencing drug absorption are application site, age, and condition of the skin. The non-keratinized dermis is more easily penetrated by an active ingredient. In the optimum topical formulations, the drug diffusion through the skin is controlled by ensuring that the drug is just soluble enough in the vehicle to encourage drug release at the desired rate.
There are several advantages of topical drug delivery systems over other conventional routes of administration such as avoidance of the first-pass metabolism, convenience, and ease of application, avoidance of risks and inconveniences of the intravenous therapy, and of diverse conditions of absorption like pH changes, presence of enzymes, gastric emptying time, easy termination of the medications, when needed, more selective and site-specific delivery of the drug, avoidance of the gastro-intestinal incompatibility, facilitating the utilization of drugs with a short biological half-life and narrow therapeutic window, improved patient compliance, suitability for self-medication, achievement of effectiveness with a lower total daily dose of the drug by continuous drug input.
Topical delivery includes two basic types of product:
a) External topical that is spread, sprayed, or otherwise dispersed onto cutaneous tissues to cover the affected area.
b) Internal topical that is applied to the mucous membrane orally, vaginally, or on anorectal tissues for local activity.
For the most part, topical preparations are used for the localized effects at the site of their application by virtue of drug penetration into the underlying layers of skin or mucous membranes. Although some unintended drug absorption may occur, it is sub therapeutics quantities and generally of minor concern.
Topical drug delivery systems include a large variety of pharmaceutical dosage forms like semisolids, liquid preparation, sprays, and solid powders. The most widely used semisolid preparation for topical drug delivery includes gels, creams, and ointments. The clinical evidence indicates that topical gel is a safe and most effective treatment option for use in the management of skin-related disease and used for local action to reduce the side effects associated with another conventional dosage form. A gel is a cross-linked polymer network swollen in a liquid medium. Its properties depend strongly on the interaction between solid-state polymer and the liquid component. Gels exhibit no steady-state flow. The interaction between polymer and the liquid dispersion medium forms an interlacing three-dimensional network of particles of the dispersed phase. The increased viscosity caused by interlacing and consequential internal friction is responsible for the semisolid state. Topical gel formulation provides a suitable delivery system for drugs because they are less greasy and can be easily removed from the skin. Gel formulation provides better application property and stability in comparison to cream and ointments.
Based on the nature of solvents, the topical gels can be categorized into different classes:
a) Hydrogel (Aqueous gels): Hydrogels are polymeric networks with a three-dimensional configuration capable of imbibing high amounts of water or biological fluids. Their affinity to absorb water is attributed to the presence of hydrophilic groups such as –OH, –CONH–, –CONH2–, and –SO3H in polymers forming hydrogel structures. Due to the contribution of these groups and domains in the network, the polymer is thus hydrated to different degrees, depending on the nature of the aqueous environment and polymer composition.

b) Xerogels: Xerogels and aerogels can be described as dried gels that retain their porous texture after drying. Xerogels are a type of solid-formed gels, which are being prepared by drying slowly at room temperature with an unconstrained shrinkage. Xerogels generally possess the properties of higher porosity and larger surface area together with very smaller pore sizes. These are prepared by the sol-gel methodology. In the sol-gel method for the preparation of xerogels, various metal alkoxide precursors, water and ethyl alcohol are required.
c) Organogels: Organogels (sometimes also referred to as oleaginous gels) are composed of both polar and nonpolar groups but the ratio of the non-polar part is very high. They may contain 35% water as the gels tend to swell in water. Organo gelators are usually low molecular weight small molecules that have the ability to thicken in organic solvents in physical organogels has grown rapidly with the discovery and synthesis of a very large number of diverse molecules, which can gel organic solvents at low concentrations.
Organogels pose various advantages over the hydrogels more specifically for the compositions comprising the active pharmaceutical ingredients that are unstable in aqueous conditions and undergo degradation in contact with water. Further, the traces of water may also facilitate the growth of microorganisms in the formulation.

There are several organogel compositions reported in the prior art:
WO2021235729 discloses an organogel complex in form of nonpolar organogel composition comprising an aromatic polymer and an aromatic organic solvent. Aromatic polymer is characterized in that polystyrene (Polystyrene). The aromatic organic solvent is selected from the phenyl alkane group (Phenyl Alkane Group) the phenyl alkane group is toluene (Toluene), phenyl ethane (Phenyl Ethane), phenyl propane (Phenyl Propane), phenyl butane (Phenyl Butane), phenyl pentane (Phenyl Pentane), phenyl hexene (Phenyl Hexane), phenyl heptane (Phenyl Heptane), phenyl octane (Phenyl Octane) and phenyl dodecane (Phenyl Dodecane).
WO2018177962 discloses a method for preparing an organogel, wherein a liquid composition is prepared, referred to as the gelling composition, comprising a solvent and a gelling agent, and capable of forming said organogel. A solid support is chosen from the group consisting of glasses, ceramics, silica, cellulosic materials, halocarbon polymers, their composites, and their mixtures. The gelling agent is chosen from the group consisting of 12-hydroxystearic acid, sorbitan esters, amides, compounds having at least one urea function, peptide compounds, and mixtures thereof.
WO2016105499 discloses a formulation for transdermal delivery of an active agent through the skin, nail, or hair follicle of a subject, which formulation comprises at least one active agent in an amount effective for the treatment of a condition in said subject and benzyl alcohol— 0.5-20% w/w of the said formulation; and lecithin organogel— 25-70% w/w of said formulation. The composition further contains an antioxidant, nonionic detergent.
WO2007103555A2 discloses transdermal delivery compositions and topical compositions for application to the skin. The transdermal delivery system includes benzyl alcohol and lecithin organogel. The composition further comprises methionine; cysteine; a mixture of amino acids comprising leucine, lysine, phenylalanine, threonine, tryptophan, valine, histidine, and arginine; at least one antioxidant; at least one cross-linking agent; and at least one metallic catalyst.

The topical gel composition is formulated using various excipients such as gel-forming agent, penetration enhancer, solvent, mucoadhesive/bioadhesive polymer, antioxidant, healing adjuvants, and surfactants. However, certain excipients may not be compatible with various drugs. Several excipients may contain peroxides. Some drugs may undergo oxidation due to the presence of peroxides in different excipients. Further, the addition of antioxidants to counteract the oxidation effect of peroxides imposes several other problems such as antioxidants can lead to the degradation of various drugs such as diltiazem to a less potent product. Also, the antioxidants may induce allergic contact dermatitis upon application to sensitive skin. Additionally, antioxidants such as vitamin E may have a detrimental effect on wound healing, as such antioxidants might negatively affect collagen synthesis. Further, in certain cases like anal fissures, there is irritation and formation of wounds. The healing agent might induce contact dermatitis on exposure to open wounds.
Further, the conventional topical gel compositions comprise certain excipients such as oils and oleaginous ingredients, which may result in oxidation of the composition. To counter such oxidation and oxidizing impurities, antioxidants are commonly added to topical gel compositions. However, the antioxidants may impose additional challenges such as drug-excipient incompatibilities and increased cost of the product.
Further, water is used as a vehicle in the topical gel composition. However, there are certain drugs that undergo hydrolysis in the presence of water. Some drugs are converted into active moieties due to hydrolysis, for example- Modafinil, Salvinorin A, Carbamazepine, Procaine, Aspirin, Clofibrate Meperidine, Enalapril, Cocaine, Lidocaine, Procainamide, Indomethacin, Suxamethonium. Whereas some drugs such as diltiazem may undergo degradation due to hydrolysis. Therefore, it is very challenging to formulate a topical gel composition for such drugs that undergoing hydrolysis. One more challenge with the aqueous composition is that it is easily wiped off from the site of application and may stick to clothes. Due to frequent removal of composition, it is required to be applied several times and this may be very inconvenient for the patients who are needed to apply the composition at certain places like the vaginal and anorectal region.
Therefore, there is still an unmet need for a topical gel composition having non-aqueous excipients, that are antioxidant-free, peroxide-free, and suitable for application to different body parts for the treatment of various conditions such as anal fissures. Also, it is challenging to formulate a composition with a combination of active ingredients, having different functionalities.
The present inventors have come up with a novel preservative-free, topical organogel composition, which is highly stable, patient-friendly, cost-effective, and is essentially free of antioxidants, healing adjuvants, and peroxide.
OBJECT OF THE INVENTION
One object of the present invention is to provide a stable topical non-aqueous organogel composition.
Another object of the present invention is to provide a preservative-free stable topical non-aqueous organogel composition wherein the said composition is essentially free of antioxidants, healing adjuvants and peroxide.
Yet another object of the present invention is to provide a preservative-free stable topical non-aqueous gel composition comprising a combination of at least two active ingredients wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxide.
Yet another object of the present invention is to provide the process of preparation of a preservative-free stable topical non-aqueous gel composition comprising a combination of at least two active ingredients wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxide.
Other objects of the present invention will be apparent from the description of the invention herein below.
SUMMARY OF THE INVENTION
The present invention provides a preservative-free stable topical non-aqueous gel composition, wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
In one aspect, the present invention provides the preservative-free, stable topical non-aqueous organogel composition comprising a combination of active ingredients wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
In another aspect, the present invention provides the preservative-free, stable topical non-aqueous organogel composition comprising the combination of at least two active ingredients and one or more excipients, wherein the said composition is free of antioxidants and peroxides. The present invention further provides the preservative-free, stable topical non-aqueous organogels composition comprising:
a) first active ingredient,
b) second active ingredient,
c) at least one gelling agent,
d) a non-aqueous solvent;
wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
The present invention also provides a process for the preparation of the preservative-free, stable topical non-aqueous organogel composition comprising the combination of active ingredients and one or more excipients, wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.
The term “composition” herein refers to the combination of one or more drug substances and one or more excipients, “drug product”, “pharmaceutical dosage form”, “dosage form,” “final dosage form” and the like, refer to a pharmaceutical composition and/or nutritional composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, tablets filled in capsule, gummies, gels, organogels, semisolid, creams, mini tablets filled in capsule, sachets containing powder or granules, pellets, liquid solutions or suspensions, patches and the like.
The term "topical" and its derivatives as used herein refer to directly laying on or spreading on the skin in need of the treatment, e.g., by use of the hands or an applicator.
The term "stable" refers to a minimal change in physical and chemical properties of the composition over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, appearance, color, and pH.
The term "non-aqueous" as used herein, means that the composition contains no, or essentially no free or unassociated or absorbed water. In certain other preferred embodiments, the composition is "substantially non-aqueous" or "substantially waterless". The term "substantially non-aqueous" or "substantially waterless" is intended to indicate that the composition has a water content below about 50%, preferably below about 25%, such as below about 10%, below about 5% or below about 1%.
The present invention discloses cost-effective, patient compliant, preservative-free, stable, topical non-aqueous organogel composition, wherein the said composition is essentially free of antioxidants and peroxide. Further, the present invention discloses a process for the preparation of a stable topical nonaqueous organogel composition.
According to the first embodiment, the present invention provides a stable topical non-aqueous composition. The topical composition is provided in the dosage form selected from the group comprising but not limited to liquids, ointments, gels, creams, and foams. In one or more embodiments, a stable topical composition is preferably in form of gel, and more preferably in the form of organogel dosage form.
Conventionally, organogel dosage forms comprise the polar or non-polar oleaginous vehicles and may comprise the aqueous ingredients. The aqueous ingredients in the composition may pose a challenge for formulating the dosage forms comprising the drugs that are prone to hydrolysis. Hydrolysis is a chemical reaction of the interaction of chemicals with water, leading to the decomposition of both the substance and water. Hydrolysis involves the reaction of an organic chemical with water to form two or more new substances and usually means the cleavage of chemical bonds by the addition of water.
Further, oxidation is one of the most common degradation pathways for pharmaceuticals. Primarily, the oxidative degradation of the active ingredient in the formulation occurs via different mechanisms such as Autoxidation (radical-mediated); Nucleophilic/electrophilic (peroxide mediated); Oxidation that is mediated by the single electron to dioxygen. Autoxidation can start a chain process when the oxidized substrate generates a reactive species that subsequently attacks additional substrate molecules. This mechanism is also known as a radical chain reaction, where the addition of oxygen gives rise to hydroperoxides and their associated peroxy radicals (ROO-) The initiation of oxidation reactions can involve the abstraction of H-atoms from various moieties of the drug substance by the impurity-derived radicals. These can result from the reaction between hydroperoxides and trace amounts of iron or copper ions, whereby the result of both of these reactions is the same.
Peroxide-mediated reactions are the second most common oxidation mechanism after autoxidation, where a drug reacts with hydrogen peroxide. Peroxides are present in commonly used excipients, and, because of this, these reactions occur in most formulations with drug substances that are susceptible to oxidation. These reactions are slow and occur under long-term storage. Hydrogen peroxide reacts with secondary and tertiary amines, thioethers, and olefins. As indicated, hydrogen peroxide can react with both secondary and tertiary amines, but the reaction is more favorable with tertiary amines. The reaction is also pH- dependent as it is slower in the protonated state. In solids, the same concept applies where drugs in the form of salts can be disproportionate to the more oxidation-prone non-ionized form.
Further, certain compounds can undergo single electron transfer to dioxygen. Compounds that are susceptible to these reactions must contain a weakly acidic hydrogen atom, which, in a basic environment, is cleaved to form a carbanion. The carbanion undergoes single electron transfer to oxygen, which forms a carbon radical and superoxide radical. The final product of this reaction is the formation of a hydroperoxide anion.
In most cases, drugs are stable in their pure form, with instability arising due to their mixing with excipients. These excipients can contain trace-level impurities which can then react with the drug. The most common impurities in excipients are peroxides. Peroxides can, in general, be either organoperoxides (ROOR-) or hydroperoxides (ROOH). All peroxides contain a very weak O–O bond, that can easily split and form hydroxyl (-OH) and alkoxy (RO-) radicals. Other reactive oxygen species, for example superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroperoxides can be formed from peroxides and radicals. Hydroperoxides and organoperoxides are the common peroxide impurities and can cause oxidative degradation of a drug. Hydroperoxides are common trace level impurities in excipients such as polyethylene glycol (PEG), povidone, and polysorbate. All of these are polymeric excipients, where peroxides are used to initiate the polymerization reaction, which leaves trace levels of peroxides as a by-product. It is then difficult to completely eliminate these from the final product.
According to the preferred embodiment, the present invention provides a stable topical composition comprising the active ingredients and excipients which are essentially free of aqueous ingredients.
In another embodiment, the present invention provides the stable topical gel composition comprising active ingredient/s and one or more pharmaceutically acceptable excipients.
In yet another embodiment, the present invention provides the stable topical gel composition comprising one or more active ingredient/s and one or more pharmaceutically acceptable excipients, wherein the said composition is essentially free of aqueous ingredients.
In yet another embodiment, the present invention provides the preservative-free, stable topical non-aqueous gel composition comprising one or more active ingredients and one or more pharmaceutically acceptable excipients, wherein the said composition is essentially free of antioxidants and peroxides.
In yet another embodiment, the present invention provides the preservative-free, stable topical non-aqueous organogel composition comprising:
a) one or more active ingredient/s,
b) one or more pharmaceutically acceptable excipients,
wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
The topical non-aqueous organogel composition according to the present invention is intended for application at various sites such as the anorectal region, vaginal region, skin, joints, facial region, or other such locations. The topical composition according to the present invention is preferably intended for application to the vaginal and anorectal regions.
The topical nonaqueous organogel composition according to the present invention comprises the active pharmaceutical ingredients selected from the different therapeutic categories including but not limited to vasodilators, calcium channel blockers, local anesthetics, anti-acne, antibiotics, anti-inflammatory, and treatment of skin disorders, such as rosacea, erythema, and combinations thereof. In one embodiment, the topical nonaqueous organogel composition preferably comprises the active ingredients selected from but not limited to vasodilators, calcium channel blockers, and local anesthetics alone or in combinations thereof.
The vasodilators according to the present invention are selected from the group comprising of but not limited to alprostadil, nitroglycerin, hydralazine, riociguat, vericiguat, nitroprusside, nesiritide, minoxidil, isosorbide dinitrate, isosorbide mononitrate, butyl nitrite, amyl nitrite and the like.
The calcium channel blockers according to the present invention are selected from the group comprising of but not limited to amlodipine, verapamil, diltiazem, nifedipine, nisoldipine, felodipine, nimodipine, isradipine, levamlodipine, clevidipine, nicardipine and the like.
The local anesthetics according to the present invention are selected from the group comprising of but not limited to dibucaine, lidocaine, mepivacaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, articaine, procaine, chloroprocaine, tetracaine, amitocaine, etidocaine and the like.
In another embodiment, the present invention provides the topical non-aqueous organogel composition comprising the active ingredients selected from the group comprising of but not limited to calcium channel blockers and local anesthetics either alone or in combinations thereof.
Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. Being a potent vasodilator, diltiazem is used clinically as an antihypertensive, anti-arrhythmic, and as an anti-anginal agent for the management of cardiovascular conditions such as hypertension, chronic stable angina, atrial fibrillation, atrial flutter. Apart from its main approved indications, diltiazem has also been used for numerous off-label indications, such as anal fissures (in topical formulations), migraine prophylaxis, pulmonary hypertension, and rest-related cramps in the lower extremities. The in vitro degradation of diltiazem hydrochloride is potentiated in an acidic medium and the high temperatures, the main degradation product is desacetyl diltiazem which has about 50% of the potency of diltiazem hydrochloride as a vasodilator.
Lidocaine is an anesthetic of the amide group indicated for the production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby affecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes.
In another embodiment, the excipients according to the present invention are selected from the group comprising of but are not limited to a gel-forming agent, penetration enhancer, solvent, mucoadhesive/bioadhesive polymer, surfactants and the like.
Gelling (Gel-forming) agents are the gel-forming agents when dissolved in a liquid phase as a colloidal mixture forms a weakly cohesive internal structure. The gel-forming agent according to the present invention is selected from the group comprising but not limited to tragacanth, pectin, starch, carbomer, sodium alginate, gelatin, gums, polyvinyl alcohol clays, and cellulose derivatives like methylcellulose, ethylcellulose, benzylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, and sodium carboxymethylcellulose and the like.
Penetration enhancers are the agents that penetrate into the skin and interact with skin constituents to promote drug flux or reversibly decrease barrier resistance. Effective penetration enhancers act by increasing the diffusion coefficient and effective concentration of the drug in the vehicle, improving partitioning between the skin and the formulation, and decreasing the thickness of the skin. This works better with the cosolvents. The penetration enhancer according to the present inventions are selected from but not limited to the group comprising Pyrrolidones (2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), alkanols (decanol), sulfoxides (DMSO), glycols (propylene glycol, PG), azones (laurocapram), surfactants, and terpenes sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, polyethylene glycol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate and the like.
The solvent employed to make up the volume of the non-aqueous topical gel composition is selected from the group comprising of but not limited to glycols such as propylene glycols, polyethylene glycols, alcohols such as ethanol, butanol, isopropanol, benzyl alcohol, lanolin alcohols, fatty alcohols, and other solvents such as ethyl acetate, oleic acid and isopropyl myristate alone or in combinations thereof.
Mucoadhesive polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl, amide, and sulfate. These groups attach to mucus or the cell membrane by various interactions such as hydrogen bonding and hydrophobic or electrostatic interactions. These hydrophilic groups also cause polymers to swell in water and, thus, expose the maximum number of adhesive sites. The mucoadhesive polymers according to the present invention are selected from the group comprising of but not limited to hydrophilic polymers such as Methyl Cellulose, hydroxyethylcellulose, HPMC, Na CMC, carbomers, thiolated polymers such as Chitosan–iminothiolane, PAA–cysteine, PAA–homocysteine, chitosan–thioglycolic acid, chitosan–thioethylamidine, alginate–cysteine, poly (methacrylic acid)–cysteine and sodium carboxymethylcellulose–cysteine, Lectin-based polymers such as Lentil lectin, peanut agglutinin, ulex europaeus agglutinin, Novel polymers such as Tomato lectin, PAA-co-PEG, PSA.
The present invention provides a preservative-free, stable topical non-aqueous organogel composition comprising:
a) first active ingredient,
b) second active ingredient
c) one or more pharmaceutically acceptable excipients,
wherein the said composition is essentially free of antioxidants, healing adjuvants and peroxides.
The present invention provides a preservative-free, stable topical non-aqueous organogel composition comprising:
a) first active ingredient,
b) second active ingredient
c) at least one gelling agent,
d) at least one non-aqueous solvent
wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
In one of the features of the present invention, the first active ingredient is vasodilator selected from the group comprising of amlodipine, verapamil, diltiazem, nifedipine, nisoldipine, felodipine, nimodipine, isradipine, levamlodipine, clevidipine, nicardipine, and combinations thereof.
In another feature of the present invention, the second active ingredient is a local anesthetic selected from the group comprising of dibucaine, lidocaine, mepivacaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, articaine, procaine, chloroprocaine, tetracaine, amitocaine, etidocaine and combinations thereof.
In yet another feature of the present invention, the gelling agent is selected from the group comprising of tragacanth, pectin, starch, carbomer, sodium alginate, gelatin, gums, polyvinyl alcohol clays, and cellulose derivatives like methylcellulose, ethylcellulose, benzyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, and sodium carboxymethylcellulose.
In yet another feature of the present invention, the non-aqueous solvent is selected from the group comprising of glycol, alcohol, and other solvent alone or in combinations thereof; wherein:
(a) the glycol is selected from the group comprising of propylene glycol, and polyethylene glycol;
(b) the alcohol is selected from the group comprising of ethanol, butanol, isopropanol, benzyl alcohol, lanolin alcohol, and fatty alcohol; and
(c) the other solvent is selected from the group comprising of ethyl acetate, oleic acid and isopropyl myristate.
In yet another feature of the present invention, the pH of the preservative-free, stable topical non-aqueous organogel composition is within the range of 2.5-4.5, preferably between 3.0-4.5, more preferably between 3.5-4.5.
In yet another feature of the present invention, the present invention provides the stable topical non-aqueous organogel composition comprising the first and second active ingredients in the concentration range of 0.5-20% w/w each, preferably within the range of 1-10% w/w each, more preferably within the range of 1-7%w/w each.
In yet another feature of the present invention, at least one gelling agent according to the present invention is within the concentration range of 0.5-15 % w/w, preferably within the concentration range of 1-10 %, more preferably within the concentration range of 1-5% w/w of the total composition.
In yet another feature of the present invention, the concentration of least one non-aqueous solvent is more than 50%w/w, preferably more than 60% w/w, more preferably more than 80%w/w of the total composition. In one of the features of the present invention, the concentration of non-aqueous solvent is 80-97% w/w of the total composition.
In another preferred feature, the present invention provides a process for the preparation of preservative-free stable topical non-aqueous organogel composition. The present invention provides a process for the preparation of stable topical non-aqueous organogel composition, wherein the said composition is essentially free of antioxidants, healing adjuvant, and peroxides.
A process for the preparation of preservative-free, stable topical non-aqueous organogel composition according to the present invention comprises various manufacturing steps including but not limited to:
a) non-aqueous cleaning of instruments,
b) addition of non-aqueous solvent,
c) addition of a suitable gelling agent to step b,
d) preparation of non-aqueous gel,
e) addition of a first active pharmaceutical ingredient,
f) addition of a second active pharmaceutical ingredient,
g) mixing and formation of final organogel composition.
wherein the said composition is essentially free of the addition of antioxidants or peroxides.
In yet another feature, the present invention provides the stable topical non-aqueous organogel composition intended for application to the anorectal region for the treatment of various anorectal disorders such as hemorrhoids, abscesses, fistula, anal fissures, anal itching, warts, and rectal prolapse.
In yet another feature, a prospective, randomized, open-label, comparative, multicentric phase III clinical study was conducted to evaluate the efficacy and safety of the fixed-dose combination of active ingredient gel against a single active ingredient in the treatment of anal fissure.
EXAMPLES
The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and not to be construed as limiting the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
The following examples illustrate the preparation of stable topical nonaqueous gel composition.
Example no. 1:
Table no. 01: Composition as per batch 001 and 002
Ingredient Batch 001 (%w/w)
(pH – 5.33) Batch 002 (%w/w)
(pH – 6.89)
Diltiazem Hydrochloride 2 2
Lidocaine Base 2 2
Sepineo P600 -- 6
Propylene Glycol -- 90
Cetostearyl Alcohol 20 --
Heavy Liquid Paraffin 12 --
Capric Caprylic Triglyceride 52.8 --
Polysorbate 60 11 --
Benzoic Acid 0.2 --

Table no. 02: Result compilation for batch 001 and Batch 002
Batch No (pH) Condition % Desacetyl Diltiazem
Batch 001 (pH 5.33) INITIAL 1.49
Batch 002 (pH 6.89) INITIAL 2.66

Example no. 2:
Table no. 03: Composition as per Batch 003 and 004
Ingredient Batch 003 (%w/w)
(pH 7) Batch 004 (%w/w)
(pH 4)
Diltiazem HCl 2 2
Lignocaine HCl 2 2
HPMC E4M 2.5 2.5
Propylene Glycol 40 45
Sodium Benzoate -- 0.07
Benzyl Alcohol 1.5 1.5
B.H.T. 0.05 --
Polysorbate 80 0.7 --
Sodium Hydroxide 0.1 --
Benzoic Acid -- 0.28
Purified Water 45 46.65

Table no. 04: pH-dependent degradation of Diltiazem Hydrochloride
Batch No Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities (Without Known) Assay pH
Lidocaine HCl Diltiazem HCl Benzyl Alcohol
Batch 003
(pH 7) Initial Initial 50.55 0.5 51.65 93.2 49.8 100.7 7
Batch 004
(pH 4) Initial Initial 0.41 ND ND 90 96.4 97.1 4.25
18D 60°C 7.99 ND ND 90.1 89.1 97.2

Example no. 3:
Table no. 05: The composition as per Batch 005
Ingredient Batch 005 (%w/w)
Diltiazem HCl 2
Lignocaine HCl 2
Carbopol 974 3
Polyethylene Glycol 400 12
Propylene Glycol 79.43
Sodium Benzoate 0.07
Benzyl Alcohol 1.5

Table no. 06: Impact of ionic polymer Carbopol based Organogel on impurity generation
Batch No Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities (Without Known) Assay
Lidocaine HCl Diltiazem HCl Benzyl Alcohol
Approach III
Organogel
Batch 005 Initial Initial 0.15 ND ND 87.8 94.7 94.7
18D 60°C 7.73 0.68 1.18 85.3 81.5 94.1

Example no. 4:
Table no. 07: The composition as per Batch 006
Batch 006 Concentration (%w/w)
Diltiazem HCl 2
Lidocaine HCl 2
Polyethylene Glycol 1450 15
Polyethylene Glycol 400 81

Table no. 08: Stability data for batch no 006
Batch No 006 Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities excluding known

PEG 400 + PEG 1450
Batch 006 Initial Initial 0.33 0.09 0.47
60C 8 Days 0.64 0.29 1.43
40C/75RH 1M 0.78 0.41 1.79
30C/75RH 1M 0.55 0.91 3.01

Example no. 5:
Table no. 09: The composition as per Batch 007
Ingredient
Batch 007 (%w/w)
(pH 4.78)
Diltiazem HCl 2
Lidocaine HCl 2
Polyethylene Glycol 1450 15
Propylene Glycol 80.5
Monothioglycerol 0.5

Table no. 10: Impurity profile in Batch 007
Batch No Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities excluding known impurity
Lidocaine HCl Diltiazem HCl
PEG1450 + PEG 400 + Monothioglycerol
Batch 007 Initial Initial 0.05 BDL BDL 100.0 103.3
40°C/75%RH 1M 0.43 0.29 @0.95 0.45 100.7 103.2
30°C/75%RH 1M 0.31 0.14 @0.95 0.20 100.6 101.8

Example no. 6:
Table no. 11: The composition as per Batch 008
Ingredient Batch no: 008 (%w/w)
(pH 4.8)
Diltiazem Hydrochloride 2
Lidocaine Hydrochloride 2
HPC MF (Klucel) 1.75
Sodium Metabisulfite 0.1
Propylene Glycol 94.15

Table no. 12: Stability compilation for batch 008
Batch No Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities excluding known impurity pH
Lidocaine HCl Diltiazem HCl
PG + HPC-MF (Klucel) + Sodium Metabisulfite
Batch 008 Initial Initial 0.06 0.05 @ 0.704 0.05 94.9 93.8 4.73
40°C/75%RH 6M 3.22 0.51@0.710
0.33@1.044 1.35 95.3 91.9 2.90
30°C/75%RH 6M 1.69 0.07@0.229 0.12 97.4 96.7 3.48

Example no. 7:
Table no. 13: The composition as per Batch 009 and 010
Ingredient Batch 009 (%w/w)
(pH 3.64) Batch 010 (%w/w)
Diltiazem HCl 2 2
Lidocaine HCl 2 2
HPC MF (Klucel) 1.75 2.5
Propylene Glycol 94.25 93.5

Table 14: Results compilation depicting stability of batch no 009
Batch No Condition Time % Desacetyl Diltiazem % Single maximum impurity % Total impurities APIs
Lidocaine HCl Diltiazem HCl
PG and Klucel MF (1.75%w/w)
Batch 009 Initial Initial 0.05 0.05 @ 0.701 0.05 98.0 98.4
60°C 7 Days 0.34 BDL BDL 96.9 97.4
60°C 21 Days 0.71 BDL BDL 98.6 97.8
40°C/75%RH 1M 0.25 0.04@0.701 BDL 97.2 97.6
30°C/75%RH 1M 0.13 0.04 BDL 97.0 97.0
40°C/75%RH 2M 0.47 0.05 @ 0.71 0.05 99.3 99.5
30°C/75%RH 2M 0.20 0.05 @ 0.71 0.05 99.4 100.3
25°C/60%RH 2M 0.18 0.06@0.77 0.11 99.5 100.7
40°C/75%RH 3M 0.72 0.05 @ 0.77 0.13 98.9 98.6
30°C/75%RH 3M 0.31 0.05 @ 0.77 0..10 99.2 100.2
30°C/75%RH 6M 0.56 BDL BDL 96.3 96.3
40°C/75%RH 6M 1.34 0.15 @ 0.709
0.40 @1.044 0.61 97.4 94.5

Table 15: Results compilation depicting stability of batch no 010
Condition Description % desacetyl diltiazem HCl % Single maximum impurity %Total impurities Excluding known Impurity % Assay
Initial Clear Gel 0.06 BDL BDL 101.8 102.2
1M_25/60 Clear Gel 0.1 0.05 0.05 100.1 100.4
3M_25/60 Clear Gel 0.17 0.06 0.11 101.0 101.2
6M_25/60 Clear Gel 0.34 BDL BDL 101.2 101.4
9M_25/60 Clear Gel 0.40 BDL BDL 101.7 102.0
12M_25/60 Clear Gel 0.43 BDL BDL 102.1 101.4
1M_30/65 Clear Gel 0.12 0.05 0.05 100.4 100.6
3M_30/65 Clear Gel 0.23 0.05 0.05 102.4 102
6M_30/65 Clear Gel 0.48 BDL BDL 99.9 99.9
9M_30/65 Clear Gel 0.60 BDL BDL 103.3 103.2
12M_30/65 Clear Gel 0.73 BDL BDL 100.9 99.7
1M_30/75 Clear Gel 0.12 0.05 0.05 99.4 99.7
3M_30/75 Clear Gel 0.24 0.05 0.05 102.1 101.7
6M_30/75 Clear Gel 0.48 BDL BDL 101.9 102
12M_30/75 Clear Gel 1.03 BDL BDL 100.6 98.6
1M_40/75 Clear Gel 0.21 0.05 0.05 100.7 100.9
2M_40/75 Clear Gel 0.39 BDL BDL 100.2 100.4
3M_40/75 Clear Gel 0.59 0.05 0.05 101.7 101.1
6M_40/75 Clear Gel 1.13 0.15 0.15 101.2 100.6

Phase III Clinical Trial:
• Phase III clinical trial conducted in 326 patients with the Fixed Does Combination of diltiazem hydrochloride 2% w/w and lidocaine hydrochloride 2% w/w gel as per protocol approved by Subject Expert Committee (SEC) and Drugs Controller General of India (DCGI).
• The FDC demonstrated superiority to diltiazem hydrochloride gel 2% w/w alone in terms of mean reduction in anal pain intensity from baseline to Day 10 in patients with anal fissures.
• A significantly higher reduction in anal pain intensity was also observed with Test Product as compared to Reference Product at all the measured time points on Day 1 as well as at subsequent visits in the study.
• The test product demonstrated the earlier onset of action as shown by a significantly higher proportion of patients experiencing pain relief in the test group at 0.5 hours compared with patients in the reference group.
• Overall, both treatment arms were well-tolerated, and no safety concerns were identified.
, Claims: 1) A preservative-free stable topical non-aqueous organogel composition comprising:
a) first active ingredient,
b) second active ingredient,
c) at least one gelling agent,
d) at least one non-aqueous solvent;
wherein the said composition is essentially free of antioxidants, healing adjuvants, and peroxides.
2) The composition as claimed in claim 1, wherein the first active ingredient is vasodilator selected from the group comprising of amlodipine, verapamil, diltiazem, nifedipine, nisoldipine, felodipine, nimodipine, isradipine, levamlodipine, clevidipine, nicardipine, and combinations thereof.
3) The composition as claimed in claim 1, wherein the second active ingredient is a local anesthetic selected from the group comprising of dibucaine, lidocaine, mepivacaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, articaine, procaine, chloroprocaine, tetracaine, amitocaine, etidocaine and combinations thereof.
4) The composition as claimed in claim 1, wherein the gelling agent is selected from the group comprising of tragacanth, pectin, starch, carbomer, sodium alginate, gelatin, gums, polyvinyl alcohol clays, and cellulose derivatives like methylcellulose, ethylcellulose, benzyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, and sodium carboxymethylcellulose.
5) The composition as claimed in claim 1, wherein the non-aqueous solvent is selected from the group comprising of glycol, alcohol, and other solvent alone or in combinations thereof; wherein:
(a) the glycol is selected from the group comprising of propylene glycol, and polyethylene glycol;
(b) the alcohol is selected from the group comprising of ethanol, butanol, isopropanol, benzyl alcohol, lanolin alcohol, and fatty alcohol; and
(c) the other solvent is selected from the group comprising of ethyl acetate, oleic acid and isopropyl myristate.
6) The composition as claimed in claim 1, wherein the pH of the stable topical non-aqueous organogel composition is within the range of 3.5-4.5.
7) The composition as claimed in claim 1, wherein the first and second active ingredients is in the concentration range of 1-7%w/w each.
8) The composition as claimed in claim 1, wherein the concentration range of gelling agent is within the range of 1-5%w/w.
9) The composition as claimed in claim 1, wherein the concentration of non-aqueous solvent is 80-97% w/w.
10) A process for the preparation of a preservative-free stable topical non-aqueous organogel composition comprising the steps of:
a) non-aqueous cleaning of instruments,
b) addition of non-aqueous solvent,
c) addition of a suitable gelling agent to step b,
d) preparation of non-aqueous gel,
e) addition of a first active pharmaceutical ingredient,
f) addition of a second active pharmaceutical ingredient, and
g) mixing and formation of final organogel composition,
wherein the said composition is essentially free of the addition of antioxidants or peroxides.