WO2022153334A1

WO2022153334A1 - Transmucosal dosage forms of foscarnet

Info

Publication number: WO2022153334A1
Application number: PCT/IN2022/050030
Authority: WO
Inventors: Indranil Nandi; Tusharmouli Mukherjee; Dinesh Kumar; Rakesh KUMAR SINGH
Original assignee: Jubilant Generics Ltd; Jubilant Pharma Holdings Inc.
Priority date: 2021-01-15
Filing date: 2022-01-13
Publication date: 2022-07-21

Abstract

The present invention relates to sublingual pharmaceutical compositions of foscarnet or its pharmaceutically acceptable salts or solvates thereof. It also relates to the process for the preparation of said compositions. It further relates to the use of sublingual pharmaceutical compositions of foscarnet for treating and/or preventing viral infections. The compositions of foscarnet prepared as per the present invention exhibit desired pharmaceutical technical attributes such as assay, disintegration, and dissolution and fulfill the unmet need to provide a sublingual formulation of foscarnet which provides enhanced patient convenience and compliance.

Description

TRANSMUCOSAL DOSAGE FORMS OF FOSCARNET

FIELD OF THE INVENTION

The present invention relates to sublingual pharmaceutical compositions of foscarnet or its pharmaceutically acceptable salts or solvates thereof. It also relates to the process for the preparation of said compositions. It further relates to the use of sublingual pharmaceutical compositions of foscarnet for treating and/or preventing viral infections.

BACKGROUND OF THE INVENTION

Foscarnet is a broad-spectrum antiviral drug used to treat viral infections primarily caused by members of the herepesviridae family such as herpes simplex virus, varicella zoster virus, Epstein- Barr virus, and cytomegalovirus, and retroviruses, including human immunodeficiency virus (HIV) and hepatitis B virus. Molecule exhibits its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases.

Foscarnet as sodium salt is marketed in the USA in the injection dosage form in 2.4 gm/100 ml strength under the brand name Foscavir® by Clinigen Healthcare (Pfizer). It is indicated for the treatment of cytomegalovirus (CMV) rhinitis and mucocutaneous acyclovir-resistant herpes simplex virus (HSV) infections (including orofacial herpes). It is chemically known as phosphonoformic acid trisodium salt and is represented by the following formula:

Foscavir® is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute. An individualized dose at the required concentration (24 mg/mE or 12 mg/mE) for the route of administration (central line or peripheral line) needs to be aseptically prepared prior to dispensing. The standard 24 mg/mE solution may be used with or without dilution when using a central venous catheter for infusion. When a peripheral vein catheter is used, the 24 mg/mL injection must be diluted to a 12 mg/mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins. Solutions thus prepared should be used within 24 hours of first entry into a sealed bottle or infusion bag. Thus, parenteral administration is invasive and is not convenient for patients, and leads to non-compliance.

An oral formulation of foscarnet would be an obvious advantage and would improve the quality of life for patients. However, foscarnet is not suitable for oral administration as it is poorly and erratically absorbed with low bioavailability of about 20%. At low gastric pH, foscarnet decomposes via an acid-catalyzed decarboxylation which leads to poor oral bioavailability.

Transmucosal dosage forms like buccal and sublingual can overcome the limitations of oral and parenteral routes of administration. However, there is an unmet need for transmucosal dosage forms like sublingual of foscarnet which is convenient to administer and facilitate improved bioavailability compared to the oral route. In the sublingual administration, a patient needs to keep the pharmaceutical composition under the tongue while the drug diffuses into the mouth, through the mucosa lining, and from there into the bloodstream.

U.S. Patent No. 4,215,113 assigned to Astra Lakemedel Aktiebolag and published on July 29, 1980, discloses sublingual tablet of foscarnet sodium (5%) with lactose (85%), talc (5%), and agar (5%). The formulation contains agar which is prone to microbial contamination and which may affect the safety and efficacy of the formulation.

Till date, no sublingual formulation of foscarnet is commercially available in USA and other regulated market. There is an unmet need in the art to provide a sublingual formulation of foscarnet which is stable, provides enhanced patient convenience and compliance.

The present inventors have developed pharmaceutical compositions of foscarnet suitable for sublingual administration. Further, the sublingual delivery of foscarnet provides consistent absorption than oral delivery. Further, the process employed in the manufacture of the dosage form of foscarnet is consistent and therefore feasible for industrial production. The prepared sublingual dosage forms are suitable for the treatment of viral infections including viral infections caused by members of the herepesviridae family such as herpes viruses, retroviruses, and hepatitis B virus.

SUMMARY OF THE INVENTION

The present invention relates to a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and process for preparing such compositions. The present invention also relates to a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients and process for preparing such compositions.

The present invention also relates to a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients selected from the group comprising diluent, binder, disintegrant, lubricant, glidant, surfactant, pH regulating agent, effervescent agent, salivating agent, solubilizing agent, surfactant, stabilizer, sweetener, preservative, flavoring, and coloring agent, filmforming agent, and solvent or mixtures thereof.

The present invention further relates to a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, which exhibit desired pharmaceutical technical attributes such as wetting time, pH, disintegration, dissolution, thickness, diameter, hardness, friability, compressibility index, assay, related substance, content uniformity, stability, patient compliance and commercially viable and other requirements also.

The present invention also relates to the use of a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for treating viral infections, particularly viral infections caused by members of the herepesviridae family.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.

As used herein, the term “composition”, or “dosage form” or “drug delivery system”, as in pharmaceutical composition, is intended to encompass a drug product comprising foscarnet and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form” and “composition of the present invention,”. It can be administered in any pharmaceutical dosage form that can be held in the mouth for a suitable period of time and permits diffusion or erosion of the drug into the mouth cavity where it can be absorbed through the mucosa lining of the mouth. Such dosage forms include transmucosal dosage forms, tablets, lozenges, sublingual tablets, sublingual capsule, sublingual film, sublingual aerosol, sublingual solution, sublingual spray, buccal tablets, mucoadhesive tablets, bioadhesive tablets, troches, pastilles, pills, viscous liquids, pastes, drops, gels, patches and the like. “Sublingual administration” may be defined herein as the therapeutic administration of a pharmaceutical composition under the tongue. Preferably, the pharmaceutical composition refers to sublingual tablets. The tablet dosage form as per the present invention can be used for both sublingual and buccal administration or any of them. In another embodiment, the composition can be film-coated or uncoated. In another embodiment, the composition can be scored or unscored tablet. Preferably, the sublingual tablet is unscored. Preferably, the pharmaceutical compositions as per the present invention are intended for immediate or quick release. Preferably, the sublingual tablet compositions as per the present invention dissolve or disperse in the mouth of a subject from about 1 second to 300 seconds. The composition is not an injectable composition and is not intended for parenteral administration.

The transmucosal dosage form (sublingual dosage and/or buccal dosage) as per the present invention is not a rapidly disintegrating tablet that releases small fragments of the composition for swallowing and drug release in the gastrointestinal tract because such a dosage form would result in first-pass metabolism of the drug and undesirable bioavailability.

As used herein, the term “foscarnet” is used in the broad sense to include not only “foscarnet” per se but also its pharmaceutically acceptable salts, solvates, esters, hydrates, isomers, enantiomers, stereoisomers, diastereoisomers, derivatives, metabolites, polymorphs, and prodrugs thereof. Polymorph may refer to various crystalline and amorphous forms, which can be characterized by methods such as melting point, X-ray diffraction pattern, Raman spectra, IR spectra, or any other method known in the art. Preferably, the salt of foscarnet is foscarnet sodium (phosphonoformic acid, trisodium salt).

The pharmaceutical compositions of the present invention comprise about 0.1 mg to about 1000 mg of foscarnet, preferably about 0.1 mg to about 500 mg, preferably about 0.1 mg to about 400 mg, preferably about 0.1 mg to about 350 mg, preferably about 0.1 mg to about 200 mg, preferably about 0.1 mg to about 150 mg, preferably about 0.1 mg to about 100 mg and more preferably about 0.1 mg to about 70 mg foscarnet as described herein. In a further embodiment, compositions of the present invention comprise about 0.1 mg to about 30 mg of foscarnet, preferably about 0.1 mg to about 20 mg. The dose may be administered one or more times a day such as from one to ten times per day. The term “excipient” means a pharmacologically inactive component such as diluents, binders, disintegrants, lubricants, glidants, surfactants, wetting agents, pH regulating agents, buffers, taste-masking agents, water-soluble and/or water-dispersible carrier materials, effervescent agents, salivating agents, antioxidants, permeation/penetration enhancers, solubilizing agents, plasticizers, acidulants, polymers, mucoadhesive agents, bioadhesive polymers, stabilizers, emulsifying agents, suspending agents, sweeteners, preservatives, flavoring and coloring agents, film-forming agents, mouth feel improvers and solvents and the like. Co-processed excipients are also covered under the scope of the present invention. Excipient may be in the form of powder or in the form of a dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics. Excipients may be present in any part (intra and/or extra granular) of the composition in any proportion.

Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to”.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more processes, and/ or steps of the type described herein and/ or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition. As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 08 to 12 percent.

The term “patient” and/or “subject” are used interchangeably herein. In some embodiments, the patient or subject is a human. In further embodiments, the patient or subject is an animal. In some embodiments, the human can be of any age such as adult, adolescent, paediatric or geriatric.

The term “viral infection” or “virus infection” or “infection” means an infection caused by a virus. The infection may be caused by any virus from herepesviridae family such as herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus, retroviruses, including human immunodeficiency virus (HIV) and hepatitis B virus.

As used herein, the term “therapeutic agent” means an agent or drug utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or allergy or disease, or infection of a patient. The composition may be administered, as the case may be, before or after the onset of a viral infection, i.e. for prophylactic or therapeutic treatment purposes, or for both.

The term “stable” refers to the compositions of the present invention, wherein the amount of the active ingredient of a formulation does not deviate from the initial amount by more than the values given in the specification or the guidelines of the common Pharmacopoeias or loss in active ingredient is less than 50% (less than 40%, 30%, 20%, 10%, 5%) of the initial content after being stored for at least 1 month, preferably for at least 2 months, preferably for at least 3 months, more preferably for at least 6 months, more preferably for at least 12 months or more preferably for at least 24 months. The stability of the composition may be evaluated at “long term” conditions 25°C/60% Relative Humidity (RH), at intermediate condition 30°C/65% RH, at “accelerated conditions” 40°C/75% RH, in the final container either measured as the loss in the content of active ingredient. Stability testing may be conducted according to the current guidelines by ICH and USFDA. In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the total impurity is less than 5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, or less than 0.5%. In a preferred embodiment of the invention, the total impurity is less than 1% or preferably less than 0.5%.

The present invention relates to transmucosal compositions of foscarnet or its pharmaceutically acceptable salts or solvates thereof.

In one embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients and process for preparing such compositions.

The present invention also relates to a pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, wherein the composition is formulated for rapid disintegration in sublingual administration.

In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, which exhibit desired pharmaceutical technical attributes such as wetting time, pH, disintegration, dissolution, thickness, diameter, hardness, friability, compressibility index, assay, related substance, content uniformity, stability, patient compliance, and other techno-commercial requirements. In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients comprising diluent, binder, disintegrant, surfactant, pH regulating agent, glidant, lubricant, solubilizing agent, sweetener and flavoring agent.

In another embodiment of the invention, the pharmaceutical composition as per the present invention is a sublingual tablet.

In one embodiment, pharmaceutical compositions of the present invention are the solid pharmaceutical compositions that rapidly disintegrate in the mouth of a subject, upon insertion into the buccal cavity or when placed under the tongue. In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the sublingual tablet is intended to disintegrate in a time range of about 1 second to 300 seconds, preferably in about 1 second to 120 seconds or in about 1 second to 60 seconds or within about 30 seconds. Rapid disintegration may include where the pharmaceutical composition is disintegrated in about 1 second to 240 seconds, preferably in about 1 second to 120 seconds or in about 1 second to 60 seconds or within about 30 seconds. Disintegration time testing for tablets can be performed in a United States Pharmacopoeia 43 (USP), tablet disintegration tester wherein a tablet is placed in a basket, which moves upward and downward in a 1 -liter beaker of water at 37±2° C.

In another embodiment of the invention, there is provided a sublingual tablet composition, wherein the sublingual tablet exhibits intended wetting time to assess the capacity of the tablets to disintegrate by swelling in water in a time range of from about 1 second to 240 seconds.

In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof in an amount from about 0.1 mg to about 70 mg and one or more pharmaceutically acceptable excipients, wherein the composition has pH from about 2.0 and about 6.5 and intended to dissolve in about 1 second to about 240 seconds in the mouth of a subject upon placement under the tongue. Preferably, the composition dissolves within about 300 seconds in the mouth of a subject upon placement under the tongue.

In another embodiment of the invention, there is provided a pharmaceutical composition for sublingual administration comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof in an amount from about 0.1 mg to about 50 mg and at least one pH regulating agent, wherein the pH regulating agent is capable to maintain the pH from about 3 and about 9. In another embodiment, the pH regulating agent is capable to maintain the pH from about 4 to about 9. The pH can be measured by the following method as 1 tablet was disintegrated in 100 mL of purified water, and pH was noted down using a calibrated pH meter. Preferably, the pH of the composition is 4 to 7.5. In another embodiment, the pH was measured by the following method: 1 tablet was taken and was added to 250mL of various media (0.01 N Hydrochloric acid, Acetate buffer, and Phosphate buffer). The solution was shaken for a suitable time (about 2 hrs.) and pH was measured using a calibrated pH meter.

In another embodiment of the invention, the disintegration or dissolution time can also be measured in-vivo by placing the tablet in the sublingual cavity and measuring, using a stopwatch, the time that elapses between the beginning of the measurement and the moment when the tablet completely disintegrated under the action of saliva and without chewing, so as to form only a viscous pulp, the patient not having to use, during all this time, any action of the jaws.

In one embodiment, foscarnet is released 80% or more within 30 minutes or within 20 minutes after administration of the composition. More preferably the composition releases at least 80% drug in 15 minutes or less. More preferably the composition releases not less than 85% drug in 5 minutes. More preferably the composition releases not less than 75% drug in 30 minutes. The sublingual tablet compositions prepared by the process as per present invention can be subjected to in-vitro dissolution evaluation according to Test 711 “Dissolution” in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high-performance liquid chromatography. In another embodiment, sublingual tablet compositions of the present invention exhibit at least 80% of drug release in 15 minutes or less in 900 ml of phosphate buffer pH 6.8, using a USP II apparatus (paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute.

In another embodiment of the invention, there is provided a pharmaceutical composition in solid form for sublingual administration comprising: foscarnet or its pharmaceutically acceptable salts or solvates thereof in an amount from about 0.1 mg to about 70 mg, and one or more pharmaceutically acceptable excipients, wherein the composition releases at least 80% of the foscarnet in 15 minutes or less when measured in 900 ml of phosphate buffer pH 6.8 using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute. In another embodiment of the invention, the compositions prepared by the process as per the present invention have a hardness from about 1 to about 70 Newtons (N), and a friability of less than 2% when measured by USP (United States Pharmacopoeia) method. Preferably, the hardness of the tablet according to the present invention is between about 15 N to 30 N. Preferably, the friability of the tablet according to the present invention is not more than 1%. Several devices can be used to test tablet hardness such as a Monsanto tester, a Strong-Cobb tester, a Pfizer tester, an Erweka tester, a Schleuniger tester, etc. Friability can be determined using a Roche friabilator for 100 revolutions at 25 rpm (revolutions per minute). In another embodiment of the invention, there is provided a sublingual tablet composition, which has a thickness of about 2 to about 10 mm. In another embodiment of the invention, there is provided a sublingual tablet composition, which has a diameter of about 2 to about 12 mm, preferably, 3 to 8 mm. In another embodiment of the invention, there is provided a sublingual tablet composition, which has a Carr's index in the range of about 1-30%, preferably about 20% value, more preferably about 5% to 15% value, which indicates good flowability.

In another embodiment of the invention, there is provided a sublingual tablet composition of foscarnet, wherein the composition has the assay in the range from 90% to 110% as measured by HPLC (High-Performance Liquid Chromatography) method using suitable column (such as Zorbax SB-C18).

In another embodiment of the invention, content uniformity of sublingual composition is within acceptable limits and met the requirements for dosage uniformity, in the acceptance value less than or equal to 15% as measured by a suitable technique such as HPLC (High-Performance Liquid Chromatography) method.

In another embodiment, the sublingual tablet composition comprises: a) about 0.1% to about 98% of foscarnet or its pharmaceutically acceptable salts or solvates thereof, and b) about 0.1% to about 90% of one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 98% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 0 to about 80% by weight of one or more diluents, c) from about 0 to about 30% by weight of one or more binders, d) from about 0 to about 20% by weight of one or more disintegrants, e) from about 0 to about 50% by weight of one or more carriers, f) from about 0 to about 5% by weight of one or more surfactants, g) from about 0 to about 5% by weight of one or more glidants, h) from about 0 to about 5% by weight of one or more pH regulating agents, i) from about 0.1% to about 5% by weight of one or more lubricants, j) from about 0 to about 5% by weight of one or more preservatives, k) from about 0.1% to about 5% by weight of one or more sweeteners, 1) from about 0 to about 20% by weight of one or more bio/mucoadhesive agent, and optionally m) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 90% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0 to about 20% by weight of one or more binders, d) from about 0 to about 10% by weight of one or more disintegrants, e) from about 0 to about 30% by weight of one or more carriers, f) from about 0 to about 2% by weight of one or more surfactants, g) from about 0 to about 2% by weight of one or more glidants, h) from about 0 to about 5% by weight of one or more pH regulating agents, i) from about 0 to about 30% by weight of one or more solubilizing agents, j) from about 0.1% to about 2% by weight of one or more lubricants, k) from about 0.1% to about 2% by weight of one or more preservatives, 1) from about 0.1% to about 2% by weight of one or more sweeteners, m) from about 0 to about 10% by weight of one or more bio/mucoadhesive agents, and optionally n) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 85% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 10% by weight of one or more binders, d) from about 0.1% to about 15% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 10% by weight of one or more pH regulating agents, g) from about 0.01% to about 3% by weight of one or more lubricants, h) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally i) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 85% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 5% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 3% by weight of one or more lubricants, g) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally h) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual composition comprising: a) from about 0.1% to about 85% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 10% by weight of one or more binders, d) from about 0.1 to about 15% by weight of one or more disintegrants, e) from about 0.01 % to about 3% by weight of one or more glidants, f) from about 0.01% to about 3% by weight of one or more lubricants, g) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally h) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 50% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 5% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 10% by weight of one or more pH regulating agents g) from about 0.01% to about 3% by weight of one or more lubricants, h) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally i) flavoring agent, mucoadhesive agent, and one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 50% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 5% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 10% by weight of one or more pH regulating agents, g) from about 0.01% to about 20% by weight of one or more solubilizing agents, h) from about 0.01% to about 3% by weight of one or more lubricants, i) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally j) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 50% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 5% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 3% by weight of one or more lubricants, g) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally h) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 50% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 10% to about 80% by weight of one or more diluents, c) from about 0.1% to about 5% by weight of one or more binders, d) from about 0.1% to about 10% by weight of one or more disintegrants, e) from about 0.01% to about 3% by weight of one or more glidants, f) from about 0.01% to about 5% by weight of one or more pH regulating agents, g) from about 0.01% to about 3% by weight of one or more lubricants, h) from about 0.01% to about 5% by weight of one or more sweeteners, and optionally i) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual tablet composition comprising: a) from about 0.1% to about 50% by weight of foscarnet or its pharmaceutically acceptable salts or solvates thereof, b) from about 5% to about 95% by weight of one or more diluents, c) from 0 to about 70% by weight of one or more solubilizing agents, d) from 0 to about 30% by weight of one or more binders, e) from 0 to about 20% by weight of one or more disintegrants, f) from 0 to about 30% by weight of one or more adsorbents, g) from 0 to about 5% by weight of one or more glidants, h) from 0 to about 10% by weight of one or more pH regulating agents, i) from about 0.01% to about 3% by weight of one or more lubricants, j) from about 0.01% to about 20% by weight of one or more sweeteners, k) from 0 to about 20% by weight of one or more flavouring agents, and optionally 1) one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, the sublingual pharmaceutical composition comprising: a) foscarnet or its pharmaceutically acceptable salts or solvates thereof in an amount of about 0.01% to about 40% by weight; b) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, sorbitol, mixture of mannitol and maize starch, or mixtures thereof in an amount from about 5% to about 85% by weight; c) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.1% to about 20% by weight; and d) at least one or more other pharmaceutically acceptable excipients.

In another embodiment of the invention, a sublingual tablet pharmaceutical composition comprising: a) foscarnet sodium in an amount of about 0.01% to about 30% by weight; b) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, sorbitol, mixture of mannitol and maize starch, or mixtures thereof in an amount from about 5% to about 85% by weight; c) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; and d) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of foscarnet sodium to disintegrant is from about 0.1: 15 to 15:0.1 and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

In another embodiment of the invention, a sublingual tablet pharmaceutical composition comprising: a) foscarnet sodium in an amount of about 15% to about 25% by weight; b) one or more diluents selected from the group consisting of mannitol, microcrystalline cellulose, maize starch, or mixtures thereof in an amount from about 20% to about 80% by weight; c) crospovidone in an amount from about 3% to about 15% by weight; and d) magnesium stearate in an amount from about 0.01% to about 3% by weight; wherein the composition has a disintegration time of about 30 to 300 seconds and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

In another embodiment of the invention, the diluent comprises one or more mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, sorbitol, mixture of mannitol and maize starch, or mixtures thereof.

In another embodiment of the invention, one or more diluents have a weight ratio of about 0.1:20 to 20:0.1. In another embodiment of the invention, the diluent is a mixture of at least two diluents present in a weight ratio of about 0.1: 10 to 10:0.1. In another embodiment of the invention, the diluent is a mixture of at least two diluents present in a weight ratio of about 4: 1. In another embodiment of the invention, the foscarnet or its pharmaceutically acceptable salts or solvates thereof and disintegrant have a weight ratio of about 0.1:15 to 15:0.1.

In another embodiment of the invention, the sublingual pharmaceutical composition comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin, and combination thereof in an amount of about 0.1 % to about 20% by weight of the composition.

In another embodiment of the invention, the sublingual pharmaceutical composition comprises one or more flavoring agents selected from the group consisting of bubble gum, peppermint, tutti-frutti, strawberry, and combination thereof in an amount of about 0.01% to about 10% by weight of the composition.

In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, wherein foscarnet has a particle size distribution D90 less than about 200 pm, D50 less than about 100 pm and Dio less than about 50 pm. Preferably, foscarnet or its pharmaceutically acceptable salts or solvates thereof has a particle size distribution D90 less than about 100 pm.

In another embodiment of the invention, the sublingual pharmaceutical composition is prepared by wet granulation (rapid mixture granulation, fluid bed granulation, spray drying), dry granulation, dry blending, dry mixing, and direct compression. Other formulation techniques are also contemplated within the scope of the present invention such as extrusion-spheronization, hot-melt extrusion, freeze-drying, spray drying, mass extrusion, and molding. In a preferred embodiment of the present invention, the composition is prepared by the wet granulation process.

In another embodiment of the invention, the solvent used in the preparation of the composition is selected from the group comprising an aqueous solvent, alcoholic solvent, hydro-alcoholic solvent, acidic solvent, ether solvent, or any mixtures thereof. In a preferred embodiment, one or more solvents used in the preparation of composition are selected from the group comprising ethanol, methanol, water, tetrahydrofuran, hydrochloric acid, or any mixtures thereof in any volume ratio.

In another embodiment of the invention, there is provided a process of preparing sublingual tablet composition of foscarnet comprising the steps of a) sifting the active agent and one or more pharmaceutically acceptable excipients through a suitable sieve followed by mixing; b) granulating the mixture of step a) with a solution (aqueous or non-aqueous solvent) optionally containing a binder; c) drying the granulated mass and optionally milling the dried granules; d) optionally mixing with other pharmaceutically acceptable excipients such as lubricant and e) compressing the granules to form the sublingual tablet.

In another embodiment of the invention, the sublingual tablet pharmaceutical composition is prepared by a process comprising the steps of: i) wet granulating foscarnet sodium, one or more diluents, and disintegrants; ii) drying the granulate obtained in step i); iii) milling the dry granulate obtained in step ii); iv) mixing the dry granulate obtained in step iii) with one or more other excipients such as magnesium stearate; and v) compressing the mixture of step iv) into a tablet to form the sublingual tablet.

In another embodiment of the invention, there is provided a process of preparing sublingual tablet composition, includes the steps of: a) sifting the accurately weighed quantities of one or more pharmaceutically acceptable excipient(s) such as diluent through a suitable sieve, b) preparing a solution or dispersion of drug in suitable solvent aqueous or non-aqueous solvent), c) granulating the mixture of step a) with a solution or dispersion of step b), d) drying the granulated mass, optionally milling of the dried granules, e) blending of dried granules with one or more pharmaceutically acceptable excipient(s) such as suitable disintegrant, glidant, sweetener, and optional flavor, and passing through a suitable sieve, f) lubricating the sifted blend of step and passing through a suitable sieve, h) compressing the lubricated granules into tablets.

In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, wherein the composition is stable.

In another embodiment of the invention, there is provided a method for the treatment of viral infections, which comprises administering to a patient the sublingual composition of foscarnet comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients.

In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, wherein the composition is agar free. In another embodiment of the invention, there is provided a sublingual pharmaceutical composition comprising foscarnet in combination with other antiviral agents such as ganciclovir and acyclovir.

In another embodiment, the present invention includes a sublingual pharmaceutical composition comprising foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more pharmaceutically acceptable excipients, wherein the composition is free of other polymorphic forms or any polymorphic form conversion.

In another embodiment of the invention, the pH regulating agent is selected such that the degradation of the active ingredient or other components of the composition is slowed or reduced.

In one embodiment, the sublingual pharmaceutical compositions as per the present invention provide a method of increasing the bioavailability of foscarnet. More particularly, sublingual pharmaceutical compositions as per the present invention allow the active agent to by-pass gastric degradation, thereby enhancing the bioavailability of the active agent. Such sublingual compositions can offer several advantages over other modes of drug delivery, including, but not limited to, increased chemical stability of the active ingredient, sufficient shelf-life, good pharmacotechnical properties, stable drug release, increasing the onset of action, lowering the required dosage, enhancing the efficacy and improving the safety profile of the active agent.

In one embodiment, the present invention provides use of sublingual pharmaceutical compositions of the present invention in method for treating, preventing, ameliorating, and/or delaying the onset of one or more symptoms associated with or resulting from a viral infection, preferably respiratory viral infection in a subject, caused by members of the members of the herepesviridae family such as herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus, and retroviruses, including human immunodeficiency virus (HIV) and hepatitis B virus.

In certain embodiments, the subject or patient is a human. In certain embodiments, the subject or patient is an adult. In certain embodiments, the subject or patient is an adolescent. In certain embodiments, the subject or patient is a child. In one embodiment, the subject or patient is of age group between one-year-old to 90 years old.

In one embodiment, the composition can be administered once daily, twice daily, thrice daily, multiple times a day, or divided into multiple daily doses from once per day to once in six months such as twice daily, three times daily, four times daily, once a week, twice in a week, thrice in a week, once in two weeks, once in three weeks, once in four weeks or like. In one embodiment, the composition is intended for at least once daily administration. In one embodiment, the sublingual pharmaceutical composition is self-administered by a patient.

In another embodiment, sublingual pharmaceutical compositions of the present invention may be packaged in HDPE bottles or glass bottles, or blister packs. Packaging material may optionally contain desiccants. The packaging material used according to the present invention favorably protects the composition from air, light, and moisture. Further, the composition of the present invention is packaged into a suitable pack together with instructions to place the dosage form under a patient's tongue or in the buccal cavity.

Any pharmaceutically acceptable granulating agent can be used for wet granulation. Preferable granulating solvents include, but are not limited to, aqueous, non-aqueous, alcoholic, hydro-alcoholic, ether, acidic solvents as a granulating liquid such as water, esters such as ethyl acetate, ketones such as acetone, alcohols such as methanol, ethanol (including ethanol 95%), isopropanol, butanol, dichloromethane, chloroform, dimethylacetamide, dimethyl sulfoxide, ether (such as tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane and combinations thereof), diethyl ether, mixtures of one or more alcohols and water and any combinations or mixtures thereof. In a further embodiment, solvents used as per the present invention are mixtures of one or more alcohol and water, in various volume ratios.

Various useful fillers or diluents include, but are not limited to, microcrystalline cellulose (MCC), sodium alginate, silicified MCC, microfine cellulose, lactitol, cellulose acetate, kaolin, glucose, lactose, maltose, fructose, sucrose, trehalose, starch, pregelatinized starch (PGS), sugar alcohols such as mannitol, D-mannitol, xylitol, maltitol, sorbitol, dextrates, dextrin, maltodextrin, compressible sugar, confectioner’s sugar, dextrose, polydextrose, simethicone, calcium carbonate, calcium sulfate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, isomalt, a mixture of microcrystalline cellulose and mannitol, mixture of mannitol and maize starch, mixture of microcrystalline cellulose and guar gum, or any mixtures thereof. The amount of diluent according to the present invention ranges from about 0 to about 95% by weight of the composition. In an embodiment, the diluent according to the present invention is present in an amount of about 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less. Various useful binders include, but are not limited to, acacia, guar gum, xanthan gum, alginic acid, sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcelulose (HPMC), hydroxyethylmethyl cellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone (PVP), ceratonia, dextrose, polydextrose, starch, gelatin, pregelatinized starch, hydrogenated vegetable oil type I, maltodextrin, microcrystalline cellulose, polyethylene oxide, polymethacrylates and mixtures thereof. Binder can be present in powder form or as a dispersion or mixture of both, in intra and/or extra granular part of the composition. The amount of binder according to the present invention ranges from about 0 to about 50% by weight of the composition. In an embodiment, the binder according to the present invention is present in an amount of about 50% or less, 40% or less, e.g. 30% or less, 20% or less, 10% or less, 5% or less.

Various useful disintegrants and/or super-disintegrants include, but are not limited to, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, povidone, crospovidone, polacriilin potassium, sodium starch glycolate, alginic acid, sodium alginate, calcium phosphate, colloidal silicon dioxide, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pre-gelatinized starch and/or combinations thereof. The disintegrant can be present in intra-granular or extra-granular part or in both (intra and extra granular) part of the composition. The amount of disintegrant according to the present invention ranges from about 0 to about 40% by weight of the composition. In an embodiment, the disintegrant according to the present invention is present in an amount of about 40% or less, 30% or less, e.g. 20% or less, 10% or less.

Pharmaceutically acceptable lubricants include, but are not limited to, stearic acid, zinc stearate, sucrose stearate, sodium benzoate, hydrogenated vegetable oil, calcium stearate, adipic acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol. The amount of lubricant according to the present invention ranges from about 0 to about 20% by weight of the composition. In an embodiment, the lubricant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less.

Various useful effervescent agents include, but are not limited to, food acids and acids such as tartaric acid, fumeric acid, citric acid, succinic acid, amalic, adipic, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, and or like. The amount of effervescent agents according to the present invention ranges from about 0 to about 90% by weight of the composition.

Various useful surfactants include, but not limited to, sodium lauryl sulphate, polysorbate (e.g. polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), cetrimide, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, polyethylene glycols, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylenepolyoxypropylene block copolymers such as poloxamer (such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), and combinations thereof. The amount of surfactant according to the present invention ranges from about 0 to about 30% by weight of the composition. In an embodiment, the surfactant according to the present invention is present in an amount of about 30% or less, e.g. 20% or less, 10% or less, 5% or less, or 2% or less.

Suitable pH regulating agents includes, but are not limited to, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt, alkaline oxides (potassium oxide, sodium oxide, barium oxide, magnesium oxide and aluminium oxide), sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, citrate, phosphate, borate salts, organic and inorganic acids such as citric acid, lactic acid, acetic acid, formic acid, oxalic acid, uric acid, malic acid, tartaric acid, succinic acid, benzoic acid, sorbic acid, ascorbic acid, phosphoric acid, boric acid, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid or hydrofluoric acid, as known in the art such as those described above, carbonate salts (sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, or magnesium carbonate), bicarbonate salts (sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate, or magnesium bicarbonate), basic amino acids (arginine, histidine, lysine, glycine), amino sugars (N- acetylglucosamine, galactosamine, glucosamine, sialic acid, or meglumine), meglumine, triethanolamine. Binary buffer systems are also included in the ambit of the present invention. The amount of pH regulating agents according to the present invention ranges from about 0 to about 20% by weight of the composition. In an embodiment, the pH regulating agents according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less. Suitable glidants include, but are not limited to, calcium silicate, magnesium silicate, magnesium trisilicate, stearic acid and its derivatives or esters like magnesium stearate, calcium stearate, and sodium stearate and the corresponding esters such as sodium stearyl fumarate, talc, colloidal silicon dioxide, tribasic calcium phosphate, starch, starch derivatives or mixtures thereof. The amount of glidant according to the present invention ranges from about 0 to about 20% by weight of the composition. In an embodiment, the glidant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less.

Various useful salivating agents include, but are not limited to, alkyl aryl sulfonates, alkyl sulfonates, alkyl sulfates, sulfonated amides and amities, sulfated and sulfonated esters and ethers, mono-, di-, and triglycerides, diacetyl tartaric esters of monoglycerides, polyglycerol esters, sorbitan esters and ethoxylates, lactylated esters, phospholipids such as lecithin, polyethoxylated esters, polyoxyethylene sorbitan esters, propylene glycol esters, sucrose esters, citric acid, malic acid, tartrate, sodium chloride, potassium chloride, and mixtures thereof. The amount of salivating agents according to the present invention ranges from about 0 to about 30% by weight of the composition.

Various useful solubilizing agents, permeation/penetration enhancers include, but are not limited to, alcohols, polyethylene glycols, cyclodextrins (cyclodextrin analogs, such as but not limited to, alpha-, beta-, and gamma-cyclodextrin analogs and their derivatives such as sulfobutylether- P- cyclodextrin (SBECD)), sodium lauryl sulfate, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone, sucrose laurate or sucrose oleate, sodium dodecyl sulfate (SDS) or palmitoyl carnitine chloride (PCC) and citric acid. The amount of solubilizing agents, permeation/penetration enhancers ranges from about 0 to about 30% by weight of the composition. In an embodiment, the solubilizing agent, permeation enhancer is present in an amount of about 30% or less, 20% or less, 10% or less, e.g. 5% or less, 3% or less, 2% or less, or 1% or less.

Various useful preservatives include, but are not limited to, citric acid, butylated hydroxy anisole, vitamin C, vitamin E, parabens (methylparaben, propylparaben), phenylethyl alcohol, sorbic acid, benzyl alcohol, alkylbenzyldimethylammonium chloride with a chain length of from Cs to Cis in the alkyl moiety, m-cresol or alkyl -4-hydroxybenzoate. The amount of preservatives ranges from about 0 to about 20% by weight of the composition. In an embodiment, the preservatives are present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less. Various useful flavoring agents include, but are not limited to, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin sodium, aromatics and/or natural oils, synthetic flavor oils, extracts from plants, leaves, flowers, fruits, and combinations thereof, commercially available orange, grape, cherry and bubble gum flavors, tutti-frutti flavours and mixtures thereof. The amount of flavoring agents ranges from about 0 to about 10% by weight of the composition. In an embodiment, the flavoring agents are present in an amount of about 10% or less, e.g. 5% or less, 3% or less, 2% or less, or 1% or less.

Various useful sweetening agents include, but are not limited to, sugars such as sucrose, sucralose, glucose, dextrose, maltose, fructose, artificial sweeteners (such as saccharin, saccharin sodium, aspartame, acesulfame, acesulfame potassium, neohesperidine dihydrochalcone, monoammonium glycyrrhizinate, thaumatin, sugar alcohols (such as mannitol, xylitol, lactitol, maltitol syrup) and mixtures thereof, present conveniently in an amount of from about 0 to about 65% by weight of the composition. In an embodiment, the sweetening agents according to the present invention is in an amount of about 65% or less, e.g. 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less.

The various useful bioadhesive/mucoadhesive agents include, but are not limited to: a) natural polymers selected from chitosan, alginate, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium hyaluronate, xanthan gum b) natural proteins selected from animal origin or vegetable origin, natural milk proteins ( like milk protein concentrate), natural pea proteins, natural soy proteins, natural potato proteins, natural wheat proteins, gliadin proteins c) synthetic polymers: carbomer, polyvinyl alcohol, acrylic polymers. The amount of bioadhesive/mucoadhesive ranges from about 0 to about 30% by weight of the composition. In an embodiment, bioadhesive/mucoadhesive is present in an amount of about 30% or less, 20% or less, 10% or less, e.g. 5% or less, 3% or less, 2% or less, or 1% or less.

Various other excipients or inert ingredients such as antioxidants, acidulants, effervescent agents, water-soluble and/or water-dispersible carrier materials, bio/mucoadhesion promoting agents, stabilizers, emulsifiers, plasticizers, suspending agents, and coloring agents are also covered under the ambit of the present invention. The amount of these excipients may range from about 0 to about 90% by the weight of the composition. In an embodiment, these excipients are present in an amount of about 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less. 5 The following examples are provided to illustrate embodiments of the disclosure but they are by no means intended to limit its scope.

EXAMPLES: Foscarnet sublingual tablets were prepared by using the quantitative formula as given in Table 1, 2, and 3 (Quantity /Tablet (%w/w))

Table 1: Examples (Ex.) 1-2:

10 Procedure: Wet granulation/ Dry granulation /Direct compression

Table 2: Examples (Ex.) 3-9:

Procedure -Table 2: i) Diluent, foscarnet (optionally pH regulating agent) are sifted through a suitable sieve, ii) surfactant (optional) is dissolved in a suitable solvent (such as water) followed by addition of binder, iii) step i) blend is granulated using the dispersion of step ii), iv) wet granules are dried followed by passing the dried granules through a suitable sieve, v) dried granules are blended with suitable excipients such as sweetener, disintegrant, glidant, flavor (optional) and lubricant and are sifted through a suitable sieve, vi) the blend of step v) is compressed into tablets using suitable punches.

Table 3: Examples (Ex.) 10-11:

Procedure -Table 3: i) Drug, diluents, and disintegrant were mixed together, ii) Blend of step i) was granulated with granulating solvent, iii) Granules of step ii) were dried, iv) Dried granules were sifted through a suitable sieve, v) Granules of step iv) were blended with lubricant, vi) The blend of step v) was compressed using suitable tooling.

Results: The results of assay, disintegration time and dissolution profile of the above formulations are presented in below table 4. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute.

Table 4

Claims

WHAT IS CLAIMED:

1. A sublingual pharmaceutical composition comprising: a) foscarnet or its pharmaceutically acceptable salts or solvates thereof in an amount of about 0.01% to about 40% by weight; b) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, sorbitol, mixture of mannitol and maize starch, or mixtures thereof in an amount from about 5% to about 85% by weight; c) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.1% to about 20% by weight; and d) at least one or more other pharmaceutically acceptable excipients.

2. The sublingual pharmaceutical composition according to claim 1, wherein the composition is a sublingual tablet.

3. The sublingual pharmaceutical composition according to claim 1, wherein the composition dissolves within about 300 seconds in the mouth of a subject upon placement under the tongue.

4. The sublingual pharmaceutical composition according to claim 1, wherein the pH of the composition is 3 to 9.

5. The sublingual pharmaceutical composition according to claim 1, wherein the pH of the composition is 4 to 7.5.

6. The sublingual pharmaceutical composition according to claim 1, wherein the amount of foscarnet or its pharmaceutically acceptable salts or solvates thereof in the composition ranges from about 0.1 mg to about 150 mg.

7. The sublingual pharmaceutical composition according to claim 1, wherein the foscarnet or its pharmaceutically acceptable salts or solvates thereof and one or more diluents have a weight ratio of about 0.1:20 to 20:0.1.

8. The sublingual pharmaceutical composition according to claim 1, wherein the diluent is a mixture of at least two diluents present in a weight ratio of about 0.1:10 to 10:0.1.

24

9. The sublingual pharmaceutical composition according to claim 1, wherein the diluent is a mixture of at least two diluents present in a weight ratio of about 4: 1.

10. The sublingual pharmaceutical composition according to claim 1, wherein the foscarnet or its pharmaceutically acceptable salts or solvates thereof and disintegrant have a weight ratio of about 0.1: 15 to 15:0.1.

11. The sublingual pharmaceutical composition according to claim 1 , wherein one or more other pharmaceutically acceptable excipients are selected from the group consisting of binder, surfactant, pH regulating agent, glidant, adsorbent, lubricant, sweetener, taste masking agent, and flavoring agent.

12. The sublingual pharmaceutical composition according to claim 1, wherein the composition is prepared by the wet granulation process.

13. The sublingual pharmaceutical composition according to claim 1, wherein the composition further comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin, and combination thereof in an amount of about 0.1% to about 20% by weight of the composition.

14. The sublingual pharmaceutical composition according to claim 1, wherein the composition further comprises one or more flavoring agents selected from the group consisting of bubble gum, peppermint, tutti-frutti, strawberry, and combination thereof in an amount of about 0.01% to about 10% by weight of the composition.

15. The sublingual pharmaceutical composition according to claim 1, further comprises from about 0.01% to about 3% by weight of one or more lubricants.

16. The sublingual pharmaceutical composition according to claim 1 , wherein the composition is self-administered by a patient.

17. The sublingual pharmaceutical composition according to claim 1, wherein foscarnet or its pharmaceutically acceptable salts or solvates thereof has a particle size distribution of D90 less than about 100 pm.

18. A sublingual tablet pharmaceutical composition comprising: a) foscarnet sodium in an amount of about 0.01% to about 30% by weight; b) one or more diluents selected from the group consisting of mannitol, lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch, maize starch, mixture of mannitol and maize starch, sorbitol, or mixtures thereof in an amount from about 5% to about 85% by weight; c) one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose, or mixtures thereof in an amount from about 0.5% to about 15% by weight; and d) at least one or more other pharmaceutically acceptable excipients; wherein the weight ratio of foscarnet sodium to disintegrant is from about 0.1: 15 to 15:0.1 and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.

19. The sublingual tablet pharmaceutical composition according to claim 18, where the composition is prepared by a process comprising the steps of: i) wet granulating foscarnet sodium, one or more diluents, and disintegrants; ii) drying the granulate obtained in step i); iii) milling the dry granulate obtained in step ii); iv) mixing the dry granulate obtained in step iii) with one or more other excipients such as magnesium stearate; and v) compressing the mixture of step iv) into a tablet to form the sublingual tablet.

20. A sublingual tablet pharmaceutical composition comprising: a) foscarnet sodium in an amount of about 15% to about 25% by weight; b) one or more diluents selected from the group consisting of mannitol, microcrystalline cellulose, maize starch, or mixtures thereof in an amount from about 20% to about 80% by weight; c) crospovidone in an amount from about 3% to about 15% by weight; and d) magnesium stearate in an amount from about 0.01% to about 3% by weight; wherein the composition has a disintegration time of about 30 to 300 seconds and the composition exhibits an in-vitro dissolution rate of not less than 75% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions.