Novel topical formulations of tofacitinib and preparation method thereof

Abstract

Novel topical formulations of tofacitinib and preparation method thereof ABSTRACT The present disclosure relates to novel topical formulations containing tofacitinib or a pharmaceutically acceptable salt’s thereof for treating dermatological conditions, such as atopic dermatitis, psoriasis, and eczema and autoimmune disorders such as rheumatoid arthritis, wherein the said formulation is a niosomes based formulation.

Specification

Description:TITLE OF THE INVENTION
Novel topical formulations of tofacitinib and preparation method thereof
FIELD OF THE INVENTION
The present invention relates to stable topical compositions comprising Tofacitinib or a pharmaceutically acceptable salt thereof, surfactant, cholesterol, and optionally one or more pharmaceutical excipients. The present invention further relates to methods of preparing and administering such pharmaceutical compositions for treating autoimmune disorders, in particular rheumatoid arthritis, psoriasis, atopic dermatitis and alopecia.
BACKGROUND OF THE INVENTION
Tofacitinib Citrate is chemically known as (3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-ß-oxo-1•piperidinepropanenitrile,2-hydroxy-1,2,3-propane tricarboxylate (1:1) and was approved by USFDA under the brand name XELJANZ® to PFIZER for treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Ulcerative Colitis in adults and Polyarticular Course Juvenile Idiopathic Arthritis in patients 2 years of age and older.
Tofacitinib is a Janus kinase (JAK) inhibitor, which was first disclosed in U.S. Pat. No. US7432370. US9937181 and US10639309 disclose tablet comprising Tofacitinib with specific excipients.
Tofacitinib Citrate oral formulation possesses adverse side effects, such as upper respiratory tract infections, headache, diarrhoea, and cold symptoms, when administrated as oral composition.
In view of the above side effects, it is therefore desirable to develop alternate dosage forms other than oral composition comprising Tofacitinib or a pharmaceutically acceptable salt thereof that are stable and having excellent bioavailability.
Alternate dosage forms includes topical formulations. Among those topical tofacitinib formulations, liposomal drug delivery systems, although successful in improving the pharmacokinetics and bioavailability of drugs, encounter challenges related to stability during storage, batch-to-batch consistency, and scalability. (Shen et al, Pharmazie. 2020 Apr 6;75(4):131-135. doi: 10.1691/ph.2020.9154. PMID: 32295688)
Hence, there remains a need to develop an alternate topical drug delivery system which provides maximum penetration of tofacitinib to treat various autoimmune disorders especially rheumatoid arthritis and psoriasis.
SUMMARY OF THE INVENTION
The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
In one aspect, the present invention discloses a pharmaceutical composition comprising tofacitinib or a pharmaceutically acceptable salt thereof within niosomes, wherein said niosomes consist of a non-ionic surfactant, cholesterol, Tofacitinib or it's salt thereof and optionally one or more pharmaceutically acceptable excipients.
In another aspect, the invention discloses topical formulations of tofacitinib in niosomes. The disclosed tofacitinib niosomes having a size of 10 nm to 1000 nm, in particular the size of niosomes are in between 100 nm to 300 nm, which help in better penetration of tofacitinib when applied topically. Further, these niosomes can be formulated as ointment, lotion, gel or cream.
The disclosed formulations of the invention are stable at room temperature for at least 6 months without any agglomerates.
The formulations of the present invention are topical formulations which are advantageous in treating autoimmune disorder such as rheumatoid arthritis and psoriasis, atopic dermatitis, and alopecia.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1. illustrates drug release studies showing % cumulative drug release (CDR) of tofacitinib citrate saturated solution and tofacitinib citrate niosomes suspension and kinetic model plots with drug release data of tofacitinib citrate niosomes suspensions; the chart showing the changes in paw volume in the groups of in vivo antiarthritic activity.
BRIEF DESCRIPTION OF THE INVENTION
The foregoing has outlined rather broadly the features and technical advantages of the present invention so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features and advantages of the invention will be described herein after that from the subject of the claims of the invention. Those skilled in the art should appreciate that they may readily use the conception, and the specific embodiment disclosed as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the invention in its broadest form.
Definitions:

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps.

The terms "a" and "an" and "the" and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

As used herein, the terms "composition(s)" and "formulation(s)" can be used interchangeably depending on the context in which they are used as would be appreciated by a person skilled in the art.
The term "room temperature" as used herein, means 20 °C to 25 °C. In an embodiment it is 20 °C. In an embodiment it is 21 °C. In an embodiment it is 22 °C. In an embodiment it is 23 °C. In an embodiment it is 24 °C. In an embodiment it is 25 °C.
As used herein, the term "gel", refers, inter alia, to a carrier or formulation or composition that is not flowable at room temperature, such that when subjected to normal gravity at room temperature, it will retain its form.
"Surfactant," "emulsifier," and "surface active agent," as used herein, do not include compounds which do not function effectively on their own to reduce surface tension between two substances or phases and stabilize an emulsion of water and oil or two phases in the system.
As used herein, the term "emollient" refers to a material or agent that, when placed in contact with the human skin, is able to soften, smoothen, reduce scaling and itching, reduce inflammation, improve skin barrier function, and/or act as a carrier for active agents. Examples of emollients include but are not limited to avocado oil, isopropyl myristate, mineral oil, capric triglycerides, caprylic triglyceride, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohols, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, unsaturated or polyunsaturated oils, olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oil, an essential oil, a silicone oil, dimethicone, cyclomethicone, polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxane copolymer, and poly(dimethylsiloxane)-(diphenyl-siloxane).
The term "Tofacitinib" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
The term, "pharmaceutically acceptable excipients" as used herein refers to solubiliser, solvents, co-solvents, preservatives, wetting agents, thickening agents, rheology modifiers or thickening agent, antifoaming agents, stabilizers, an antioxidant, a chelating agent, an oil phase, an emulsifier, a penetration enhancer, a pH adjusting agent, a preservative, an antimicrobial agent, an opacifier, a fragrance, a colorant, a gelling agent, a moisturizer, a surfactant and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.
The term "Topical composition" or "pharmaceutical composition" or "dosage form" as used herein synonymously include topical dosage forms such as a solution, a suspension, a cream, an ointment, a lotion and a gel. Preferably, the topical formulation is a solution or a gel. More preferably, the topical formulation is a gel.
The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
As used herein the term "niosome" is a non-ionic surfactant-based liposome. Niosomes are formed mostly by cholesterol incorporation as an excipient. Niosomes have more penetrating capability than the emulsions. They are structurally similar to liposomes in having a bilayer, however, the materials used to prepare niosomes make them more stable and thus niosomes offer many more advantages over liposomes. Niosomes are lamellar structures that are microscopic in size. They constitute of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. The surfactant molecules tend to orient themselves in such a way that the hydrophilic ends of the non-ionic surfactant point outwards, while the hydrophobic ends face each other to form the bilayer.
Before undertaking the detailed description of the invention below it may be advantageous to set forth definitions of certain words and phrases used throughout this patent document: the terms "include" and "comprise " as well as derivatives thereof mean inclusion without limitation; the term "or " is inclusive meaning and/or; the phrases "associated with" and "associated therewith " as well as derivatives thereof may mean to include be included within interconnect with contain be contained within connect to or with couple to or with be communicable with cooperate with interleave juxtapose be proximate to be bound to or with have a property of or the like; and the term .
In one embodiment, the present invention discloses a stable pharmaceutical composition comprising tofacitinib or a pharmaceutically acceptable salt thereof within niosomes, wherein said niosomes comprises a non-ionic surfactant, cholesterol, Tofacitinib or it's salt thereof and optionally one or more pharmaceutically acceptable excipients.
In the above mentioned embodiment, the formulation is a topical formulation and further comprises a carrier base and at least one emollient.
In any of the above mentioned embodiments of the invention, the pharmaceutical composition as claimed in claim 1, wherein the tofacitinib salt is a citrate salt, hydrochloride salt, hydrobromide salt, oxalate salt, nitrate salt, sulfate salt, phosphate salt, fumarate salt, succinate salt, maleate salt, besylate salt, tosylate salt, palmitate salt, tartrate salt, adipate salt, laurate salt, or myristate salt.
In any of the above-mentioned embodiments of the invention, wherein the concentration of non-ionic surfactant typically ranges from 10%w/w to 30%w/w of the total formulation and the ratio between non-ionic surfactant to cholesterol ranges from 1:1 to 8:1.
In any of the above mentioned embodiments of the invention, the non-ionic surfactant is selected from the group consisting of sorbitan monolaurate, Sorbitan monopalmitate, sorbitan monostearate, polyethylene glycol sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate.
In any of the above mentioned embodiments of the invention, the non-ionic surfactant concentration present in the niosomes is within the range of 10 mg to 50 mg.
In any of the above mentioned embodiments of the invention, the invention, cholesterol concentration present in the niosomes is within the range of 1 mg to 20 mg.
In any of the above mentioned embodiments of the invention, the pharmaceutically acceptable excipients are charge inducers, organic solvents, aqueous carrier, buffer and stabilizer.
In the above mentioned embodiment, the charge inducer is selected from the group consisting of dicetyl phosphate, dihexadecyl phosphate, lipoamine acid, stearyl amine, cetylpyridinium chloride.
In any of the above mentioned embodiments, the stabilizer is selected from the group consisting of cholesterol, pluronic F-127, span-60, stearyl amine, Dicetyl phosphate tocopherol, polyethylene glycol, sodium alginate.
In yet another embodiment, the invention discloses a topical pharmaceutical composition comprising tofacitinib or a pharmaceutically acceptable salt thereof within niosomes, wherein the said niosomes comprises of a 10 mg to 50 mg non-ionic surfactant, 5 mg to 15 mg cholesterol, 3 mg to 8mg Tofacitinib or it's salt thereof and optionally one or more pharmaceutically acceptable excipients wherein the niosomes have a particle size ranging from 100 to 1000 nm.
In a furthermore embodiment of the invention discloses a topical pharmaceutical formulation of Tofacitinib-niosome gel comprising
a) the drug tofacitinib or a pharmaceutically acceptable salt thereof within niosomes or loaded into niosomes and
b) one or more following pharmaceutically acceptable excipients selected from the group consisting of gelling agent; solvents/co-solvents; penetration enhancers; pH adjusting agents; preservatives; humectants and, emollients, antioxidants, colorants, and fragrances.
In another embodiment of the invention discloses, a topical pharmaceutical formulation of Tofacitinib-niosomes gel comprising:
a) the drug tofacitinib or a pharmaceutically acceptable salt thereof loaded or within niosomes;
b) gelling agent;
c) solvents/Co-solvents;
d) penetration enhancers;
e) pH adjusting agents;
f) preservatives;
g) humectants and,
h) optionally comprising one or more pharmaceutically acceptable excipients selected from the group consisting of emollients, antioxidants, colorants, and fragrances.
In any of the above mentioned embodiments, the formulation is stable at room temperature without any agglomerates.
In any of the above-mentioned embodiment of the invention, the gelling agent is selected from the group consisting of Carbopol 934, 940, HPMC, or Xanthan gum.
In any of the above-mentioned embodiment of the invention, the solvents/co-solvents is selected from the group consisting of water, ethanol, or propylene glycol.
In any of the above-mentioned embodiment of the invention, the penetration enhancer is selected from the group consisting of ethanol, oleic acid, propylene glycol, dimethyl sulfoxide, urea, azone, isopropyl myristate, menthol, carbomer, SLS, lecithin, capsaicin, transcutol, polysorbate-80, or tween-20.
In any of the above-mentioned embodiment of the invention, the pH adjusting agent is triethanolamine,
In any of the above-mentioned embodiment of the invention, the preservative is selected from the group consisting of parabens, or phenoxyethanol.
In any of the above-mentioned embodiment of the invention, wherein the humectant is glycerin.
In any of the above-mentioned embodiment of the invention, the disclosed tofacitinib formulation is a gel, ointment or cream, lotion, pastes, patches, sprays, foams.
In any of the above-mentioned embodiment of the invention, the formulation has a pH between 4.5 to 6.5.
In any of the above mentioned embodiments of the invention, the particle size of tofacitinib-niosomes is in the range of 10 nm to 1000 nm.
In any of the above mentioned embodiments of the invention, the particle size of tofacitinib-niosomes is in the range of 100 nm to 500 nm.
In any of the above mentioned embodiments of the invention, the particle size of tofacitinib-niosomes is in the range of 150 nm to 300 nm.
In any of the above mentioned embodiments of the invention, the disclosed formulations are stable at 22 ° C -25 ° C for a period of time includes at least one month.
In any of the above mentioned embodiments of the invention, the disclosed formulations are free of any agglomerates.
In any of the above mentioned embodiments, the disclosed formulations are useful for the treatment of autoimmune disorders such as rheumatoid arthritis psoriatic arthritis, ulcerative colitis, poly articular course juvenile idiopathic arthritis, ankylosing spondylitis atopic dermatitis.
The invention specifically discloses tofacitinib or a pharmaceutically acceptable salt thereof niosomes. The niosomes possess qualities like biodegradability, non-toxicity, ability to alter drug behavior in the body. Niosomes facilitate drug penetration into the skin and prolong their presence, thereby reducing systemic absorption. This can be advantageous in regulating drug effects within the body. When niosomes are applied to the skin, they enhance the properties of the outermost skin layer by decreasing its water loss. Additionally, the attachment and merging of niosomes with the skin elements will enhance the drug's thermodynamic activity gradient, affecting drug permeation.
In any of the above mentioned embodiments of the inventions, the niosomes comprising tofacitinib or pharmaceutically acceptable salt thereof in the topical formulation is present at a concentration from about 0.1% w/w to about 5% w/w, preferably about 1% w/w to about 4% w/w, based on the total weight of the formulation.
The topical formulation as disclosed in the present invention has following advantages. First advantage is that, tofacitinib-niosomal formulations are stable as compared to ethosomes and liposomes. Tofacitinib loaded ethosomes showed visible sedimentation within 7 days of preparation. In contrast, Tofacitinib -niosomes solution remained stable for 180 days at low temperature without any significant changes in the vesicles size, Polydispersity index (PDI), and zeta potentials. The amount of Tofacitinib in tofacitinib-niosomes was reduced to 97% at 45° C after 120 days of storage, whereas the Tofacitinib liposomes have shown a reduction in tofacitinib content to 89% after 120 days of storage at the same temperature.
The disclosed formulation of the invention delivers the drug tofacitinib or salt thereof in a sustained release manner. Improved drug release was observed in Invitro drug release studies conducted for Tofacitinib-niosomes over the free drug solution. 50.3% burst release was shown in the first 30 minutes of release study from free drug solution and 83.2% in 24 hours whereas 34.8% was the release from Tofacitinib-niosomes in first 30 min and 100% released in 24 hrs, showing a sustained release and a complete release.
Tofacitinib-Niosomes gel formulation has shown an improved drug release and % cumulative drug release (CDR) in in vitro drug release studies of niosomal gel and free drug gel were 66.5% and 33.6% respectively in the first 8 hrs.
The localized delivery system reduces systemic exposure and risk of serious side effects. Further, the localized drug delivery improves efficacy at the target site.
The disclosed formulations of the invention are more convenient and patient-friendly and allows for safer long-term use in managing chronic conditions
Certain specific aspects and embodiments of the invention are more fully described by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention in any manner.

Examples
Example 1: Preparation of Tofacitinib citrate Niosomes(TN)
Ethanol injection method was used to fabricate tofacitinib citrate niosomes. Preparation procedure in brief, Span 60 and cholesterol were dissolved in 2 ml of ethanol over a bath sonicator to obtain a clear solution. Tofacitinib citrate and pluronic-F127 were added to phosphate buffer (pH 7.4)- the hydrating solution, in a separate beaker. The organic solution was added drop-wise into the aqueous solution maintained at 60-65° C with a syringe plunger at a 1 ml/min rate while continuously stirring at 850 rpm, using a magnetic stirrer. Vesicle formation occurs at the temperature above the transition temperature, and the evaporation of the organic phase at the interphase between the two phases results in niosomes. Stirring was continued at the same temperature maintained over a hot mantle, for 45 min and later at room temperature for 2 hrs, for pruning and stabilization of niosomes to take place.
After a keen understanding of the influential factors in niosomes preparation from the preliminary trials, the variable parameters that crucially affect the quality of niosomes were enlisted. Optimization studies were conducted by applying these factors in Box-Behnken design (BBD) design model developed using Design-Expert 13 software, which is an appropriate model in statistical validation techniques of quadratic Response surface methodology when more complexity of multiple factors and responses exit. The independent variables were the span 60 concentration (A), cholesterol concentration(B), hydration volume (C) and the dependent variables being particle size (nm):(Y1), polydispersity index:(Y2), and the entrapment efficiency:(Y3) as responses, studied in a total of 17 formulation batches suggested by the Design expert. An average of triplicate values of responses for each formulation batch were taken and proceeded for optimization data analysis.
Table 1 shows the responses of formulation batches.
Characterization of formulation batches
The formulation batches thus prepared were assessed for the responses comprehended as dependent variable constraints.
Particle size(PS) and Polydispersity index (PDI)
PS, and PDI, could be analysed in one setting in Zeta sizer and zeta potential (ZP) in the other, and these parameters were assessed for the formulation batches using ZS 90 in a dynamic light scattering approach (Malvern instruments, UK).
Analytical method development
Quantification of Tofacitinib citrate at various instances during the evaluation was availed with the RP-HPLC method developed to plot the Tofacitinib citrate calibration curve. An isocratic mobile phase used was Methanol: Water in 70:30 ratio and using C18 column, a detection wavelength at 289 nm, peak retention time was 4.7 min.


Entrapment efficiency
An indirect method of estimation was used for finding the entrapment efficiency of formulated batches of niosomes wherein the trapped drug quantity of Tofacitinib citrate in the niosomal sediment was obtained by subtracting the quantity of untrapped Tofacitinib citrate in supernatant solution, after centrifugation, from the amount of total drug added to the formulation and indicates the efficiency of delivery system to uptake and hold the drug into its constitution.
%Entrapment Efficiency = [(Total Tofacitinib citrate E-Free Tofacitinib citrate in Supernatant) / (Total Tofacitinib citrate)] × 100

Table 1: Results of evaluation parameters of formulation batches of Tofacitinib citrate loaded niosomes (TN)
Factor A Factor B Factor C Response Y1 Response Y2 Response Y3
Formulation code SPAN60 (mg) CHOL
(mg) HYDRATION
(ml) PS (nm) PDI EE (%)
TN1 20 15 10 170.5 0.27 71
TN2 20 5 10 196.8 0.28 75
TN3 40 5 10 212.3 0.33 84
TN4 30 10 10 162.3 0.21 78
TN5 40 15 10 230.9 0.26 83
TN6 20 10 15 152.4 0.23 76
TN7 30 15 5 250.2 0.31 75
TN8 30 5 5 258.9 0.35 73
TN9 30 10 10 193.4 0.19 80
TN10 40 10 5 260.7 0.31 77
TN11 30 10 10 177.1 0.21 84
TN12 30 15 15 176.6 0.28 80
TN13 30 10 10 161.2 0.19 78
TN14 20 10 5 240.9 0.36 72
TN15 30 10 10 175.1 0.21 83
TN16 40 10 15 201.8 0.32 88
TN17 30 5 15 171.8 0.33 76

Example 2 Stability of niosomal tofacitinib citrate formulation
The optimised formulation batch of Tofacitinib citrate niosomes was assessed for physical and chemical stability according to ICH guidelines, at varied conditions of storage (2-8°C, 25 ± 2°C, 45 ± 2°C), in a humidity chamber, for three months and a regular monitoring for changes in size of particles and EE% was carried out to assess the stability of the formulation.
Stability studies were conducted following a standard protocol, for a definite period. The results of assessed parameters did not show any significant changes, at low temperatures. Sedimentation and rise in particle size were observed, which could be because of particle aggregation, discharge of drug from vesicles, and also a decrease in EE%, sooner after one month of storage at 45 ± 2°C and later, at 25 ± 2°C. Physical instability and microbial mould growth were observed when stored at temperatures other than cool temperature, after 180 days, most apparently because cholesterol is an accommodable media for microbial growth at favourable temperatures, appealing a requirement of the addition of stabilizer and preservative.
Tofacitinib citrate loaded ethosomes showed visible sedimentation within 7 days of preparation. In contrast, Tofacitinib citrate-niosome solution remained stable in 180 days at low temp without any significant changes in the vesicles size, PDI, and zeta potentials. The amount of Tofacitinib citrate was reduced to 96% at 45° C after 120 days of storage, the improved Tofacitinib-niosomes stability may be ascribed to the presence of co-surfactant and right proportion of cholesterol which increases the rigidity and prevents leakage, deterioration and degradation thus improving the stability. Murphy et al reported improved stability of Tofacitinib citrate with glycerin in gel formulation, which was further improved by addition of antioxidants (Murphy et al., 2012)
Example 3: In Vitro release study of Tofacitinib niosomes
In vitro release studies were conducted using a dialysis sac technique.
A 2 ml of tofacitinib citrate niosomal suspension, equivalent to 0.6 mg of tofacitinib citrate was placed in the dialysis bag of nitrocellulose membrane, priorly tied on one side properly so as to not to allow any leakage. The other end of the tubing was also tied after placing the formulation under study and was kept submerged in the beaker containing release medium-PBS buffer (pH 7.4), maintained at 37 ± 1°C, and a stirring speed of 70 rpm. Samples were drawn at regular time intervals, for HPLC analysis, and replaced an equivalent quantity of fresh buffer for balancing the sink condition. The release data was interpreted in different mathematical models to understand the release profile of tofacitinib citrate from tofacitinib citrate-loaded niosomes to compare with that of the free- tofacitinib citrate drug solution examined in similar test conditions.
Example 4: Preparation and characterization of Tofacitinib citrate Niosomal gel (Tofacitinib citrate Niogel)
Tofacitinib citrate niosomes concentrate was obtained by centrifuging the suspension of niosomal formulation for 20 min at 20,000 rpm and discarding the supernatant portion with unentrapped Tofacitinib citrate and the niosomal concentrate thus obtained was resuspended into water. Carbopol 934 was the gelling agent used. A 1% hydrogel was prepared by dispersing a niosomal concentrate along with the gelling agent into a relevant quantity of water, soaking and incubating for 6 hours while continuously mixing, and finally adjusting the pH using 0.5% triethanolamine. A visual inspection of the gel's colour and texture was conducted.
A digital pH meter (model CPH 102) was used to measure the pH of Tofacitinib citrate-Niogel after a predetermined amount of gel had been appropriately diluted in distilled water. Using a Brookfield Viscometer, spindle 64 (DV-III, USA), the viscosity of the produced gel was measured. 0.5 gm samples from different portions of the formulations were obtained and individually dissolved in PBS of pH 7.4 before being evaluated by HPLC to ascertain the percentage drug content and homogeneity.
Example 5: In vivo anti-arthritic activity of Tofacitinib citrate Niosomal gel
The induction of arthritis in male Wistar rats was accomplished using Freund's complete and incomplete adjuvant factor. For the study, four groups, each containing 6 animals were used, among which one group served as the normal control (group-1) (NC), and one was the disease control (group-2) (DC). Two were treatment groups (TG). Arthritis was induced in three groups, except NC, with 0.1 ml of Freund's complete Adjuvant (FCA) injected in the sub-plantar region of the right hind paw and incomplete Freund's factor into the same paw as a booster dose on the 7th day. The NC group remained unimmunized. Development of arthritis was confirmed through visual observations, measurement of inflammation, joint and paw swelling, and estimation of arthritic score, indicating an established RA condition. The study continued with bis-in-die topical treatment of two animal groups using tofacitinib citrate niogel (group-3) and tofacitinib citrate niogel (group-4) for 14 days starting from the 14th day of disease inoculation with FCA. Throughout the study period, arthritic scores, paw volumes, and joint stiffness were regularly assessed. The disease control (DC) group and the treatment groups have shown an increase in the paw volume after the FCA inoculation. In treatment groups, the paw inflammation gradually reduced upon treatment with Tofacitinib citrate gel and Tofacitinib citrate nio gel, separately to the groups, and in the DC group, it was sustained throughout the study period. Changes in the paw volume are depicted in the chart in Figure 1.


, Claims:Claims
I/We claim

1. A pharmaceutical formulation comprising:
tofacitinib or a pharmaceutically acceptable salt thereof within niosomes, wherein said niosomes comprises of a non-ionic surfactant; cholesterol; Tofacitinib or its salt thereof; and, optionally one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the formulation is a topical formulation.

3. The pharmaceutical composition as claimed in claim 2, further comprises a carrier base and at least one emollient.

4. The pharmaceutical formulation as claimed in claim 1, wherein the tofacitinib salt is a citrate salt, hydrochloride salt, hydrobromide salt, oxalate salt, nitrate salt, sulfate salt, phosphate salt, fumarate salt, succinate salt, maleate salt, besylate salt, tosylate salt, palmitate salt, tartrate salt, adipate salt, laurate salt, or myristate salt.

5. The pharmaceutical formulation as claimed in claim 1, wherein the concentration of non-ionic surfactant typically ranges from 10%w/w to 30%w/w of the total formulation and the ratio between non-ionic surfactant to cholesterol ranges from 1:1 to 8:1.

6. The pharmaceutical formulation as claimed in claim 1, wherein the non-ionic surfactant is selected from the group consisting of sorbitan monolaurate, Sorbitan monopalmitate, sorbitan monostearate, polyethylene glycol sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate.
7. The non-ionic surfactant as claimed in claim 5, wherein the surfactant concentration is within a range of 10 mg to 50 mg.
8. The pharmaceutical formulation as claimed in claim 1, wherein the cholesterol concentration is within a range of 1 mg to 20 mg.

9. The pharmaceutical formulation as claimed in claim 1, wherein the pharmaceutically acceptable excipients are charge inducers, organic solvents, aqueous carrier, buffer and stabilizer.

10. A topical pharmaceutical composition comprising tofacitinib or a pharmaceutically acceptable salt thereof loaded niosomes, wherein the said niosomes consist of a 10 mg to 50 mg non-ionic surfactant, 5 mg to 15 mg cholesterol, 3 mg to 8mg of Tofacitinib or it's salt thereof and optionally one or more pharmaceutically acceptable excipients wherein the niosomes have a particle size ranging from 100 nm to 1000 nm.

11. The topical formulation as claimed in claim 1 or 9, wherein the formulation is stable at room temperature without any agglomerates.

12. A topical pharmaceutical formulation of tofacitinib niosome gel comprising;
a) tofacitinib or a pharmaceutically acceptable salt thereof within noisome and
b) one or more following pharmaceutically acceptable excipients selected from the group consisting of gelling agent; solvents/co-solvents; penetration enhancers; pH adjusting agents; preservatives; humectants and, emollients, antioxidants, colorants, or fragrances.

13. The formulation as claimed in any of the preceding claims, has a pH between 4.5 to 6.5.

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