DESC:FIELD OF THE INVENTION

The present invention relates to sublingual films of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of 3-80µg/cm2/min through biological mucosal membranes equivalent to human oral mucosa.

BACKGROUND OF THE INVENTION

Salbutamol Sulphate [(RS)-l-{4-hydroxy-3-hydroxymethyl phenyl)-2-(tert-butylamino) ethanol Sulphate], a selective ß2-adrenergic agonist and bronchodilator, is one of the widely used drugs for the treatment of the most respiratory diseases arising due to airway obstruction. At therapeutic doses, Salbutamol acts on the ß2- adrenoreceptors of bronchial muscle with little effect on ß1- adrenoreceptor of cardiac muscle. In the airway, activation of ß2-receptors results in relaxation of bronchial smooth muscle resulting in a bronchodilation.

Due to its fast onset of action, it is particularly suitable for management and prevention of attack in mild asthma and for the treatment of acute exacerbations in moderate and severe asthma. Asthma is a chronic inflammatory disease that results from narrowing of air tubes due to bronchial hyperactivity and bronchospasm created by hyper responsiveness of tracheo-bronchial smooth muscle to variety of stimuli. Accompanied by increased secretions and mucosal edema, it leads to breathlessness or dyspnea, wheezing cough, chest congestion and anxiety of breathlessness.

The preferred mode of administration of Salbutamol is via:
1. Direct Lung Administration through aerosol systems such as Inhalers or Nebulizers;
2. Oral administration through tablets, capsules, oral liquids; or
3. Sublingual administration through dissolving film/strips

1. Direct Lung Administration through aerosol systems such as Inhalers or Nebulizers: Salbutamol is delivered via aerosol systems such as Inhalers or Nebulizers where the mist is orally taken by mouth for more direct effect persisting for about 3-6 hours after inhalation. The inhaler forms include metered dose inhalers (MDIs), nebulizers or other proprietary delivery devices. In these forms of delivery, the maximal effect of Salbutamol can take place within 5 to 20 minutes of dosing. The main disadvantages of using aerosol systems include inaccuracy in dosing as such modes require correct actuation and inhalation coordination to deliver accurate dose, patient compliance, frequency of administration, and cost of the preparation. The aerosol systems are specific but fail to deliver the actual dose of drug with only 10% of administered dose deposited on the bronchi while rest of the drug is deposited in oropharynx and is swallowed. Further, the metered dose system is less portable while dry powder inhalers cause clogging of device and require skilful operation.

2. Oral administration through tablets, capsules, oral liquids: Salbutamol is readily absorbed from the gastrointestinal tract but it undergoes rapid and complete first-pass metabolism following oral administration, resulting in reduced systemic bioavailability of about 50%. The drug is extensively metabolized in the liver, principally to the inactive metabolite, SAL 4’-O-sulphate. The duration of Salbutamol effect generally persists for 12 hours after oral administration (depending on dosage form) and its serum half life in humans has been reported as 2.7 to 5 hours.

3. Sublingual administration through dissolving film/strips: In sublingual administration route, the drug placed under the tongue reaches directly into the blood stream through ventral surface of the tongue and floor of the mouth. Through the reticulated vein which lies underneath the oral mucosa, the drug is rapidly absorbed and transported through the facial, internal jugular and braciocephalic veins to be drained in to systemic circulation.

The sublingual route usually produces a faster onset of action than orally ingested forms as the drug is absorbed through the sublingual blood vessels bypassing the hepatic first-pass metabolic processes. The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane. For sublingual formulations, the small volume of saliva is usually sufficient for disintegration in the oral cavity. The absorption of the drug through the sublingual tablet route is 3 to 10 times greater than oral route which could be surpassed only by hypodermic injection. Peak blood levels of most products administered sublingually are achieved within 10-15 minutes, which is generally much faster than when those same drugs are ingested orally. Sublingual absorption is efficient. The percent of each dose absorbed is generally higher than that achieved by means of oral ingestion.

Sublingual drug delivery through the sublingual mucosal membranes covers the ventral side of the tongue and the soft palate. Out of the total surface area of the oral cavity (approximately 214.7cm2 ± 12.9cm2), non-keratinised epithelia involved in the sublingual delivery amounts to 37.32 cm2. In terms of permeability, the sublingual area of the oral cavity is more permeable than the buccal (cheek) area, which in turn is more permeable than the palatal (roof of the mouth) area. The differences in permeability are generally based on the relative thickness, the blood supply, and degree of keratinization of these membranes. In addition to the differences in the permeability of the various mucous membranes, the extent of drug delivery is also affected by the physicochemical properties of the drug to be delivered.

Hence, amongst the drug delivery options, despite its challenges, oral sublingual drug delivery administration is by far the most preferred route. Research efforts in the oral drug delivery segment have led to the recent development of oral fast dissolving film/strips. This form of oral mucosal drug delivery is an alternative method of drug delivery that offers several advantages over injectable, inhalable and enteral methods.

One of the main advantages of oral mucosal drug delivery is direct absorption of the administered drug through the oral mucosa, which is highly vascularized, leading to direct systemic circulation and, by-passing the gastrointestinal tract and first-pass metabolism in the liver.

Various types of sublingual dosage forms like tablets, films and sprays were developed to overcome the difficulty in swallowing conventional tablet, among pediatric, geriatric and psychiatric patients with dysphagia.

Problem associated with the sublingual tablet formulation is that there is always a risk that the patient will swallow part of the dose before the active substance has been released and absorbed locally into systemic circulation. This could result in an unwanted prolongation of the pharmacological effect.

Salbutamol drug in preferred low dosage can be delivered in an oral, quick disintegrating dosage form since the disintegration and dissolution of the dosage form occurs rapidly, thus providing rapid onset of action without any lag time. The patient can ingest the dosage from anywhere and at anytime without the aid of water which would be helpful especially in cases of unavailability of water, motion sickness, sudden episodes of allergic attacks or deglutition problems.

However, the present formulations of oral drugs do not have appreciable diffusion flux and they delay or slow thedelivery of active substances into bloodstream.

Hence, there is a need for formulation in the form of oral film/strip that provides convenience of dosing, portability and wider acceptability by pediatric as well as geriatric population.

The present invention addresses the disadvantages of state of the art as the disclosed sublingual films lead to rapid disintegration and dissolution along with its ease of swallowing property. The sublingual films aid in quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa.

OBJECTS OF THE INVENTION

Accordingly, the main object of the invention is to provide a formulation of sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 3-80?g/cm2/min.

Yet another object of the invention relates to pharmaceutical sublingual films of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and water soluble polymeric components.

Yet another object of the invention relates to pharmaceutical sublingual film of Salbutamol with reduced drug load to deliver optimum diffusion flux for quick relief to the asthmatic patients in an effective and convenient sublingual dissolving film.

Yet another object of the invention relates to pharmaceutical sublingual films of Salbutamol delivering target flux amounts with dosage as low as 0.5mg/unit via sublingual delivery.

Still another object of the invention relates to a process for preparation of pharmaceutical sublingual films of Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient, and water soluble polymeric components.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides formulation and method of preparation of pharmaceutical sublingual films of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of about 3-80?g/cm2/min.

In one embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising 4mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux of about 40-75µg/cm2/min.

In an another embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising 2mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux of about 18-35µg/cm2/min.

In further embodiments of the invention, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising 1mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux of about 4-15µg/cm2/min.

In further embodiments of the invention, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising 0.5mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux of about 3-9µg/cm2/min.

In another aspect, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient, and water soluble polymeric components.

In one embodiment of the invention the pharmaceutical sublingual film further optionally comprises of other pharmaceutically acceptable excipients selected from muco-adhesive agents, plasticizers, surfactants/non ionic solubilizers, flavours, sweeteners and colour additives.

In another embodiment of the invention, the “water soluble polymeric components” ranges about 5% to 75%w/w of the total weight of pharmaceutical sublingual film of Salbutamol, preferably about35% to 75%w/w of the total weight of pharmaceutical sublingual film of Salbutamol and more preferably about40% to 70% w/w of the total weight of pharmaceutical sublingual film.

In preferred embodiments, the water soluble polymeric components comprises polyethylene oxide, hydrophilic cellulosic polymer (HPMC) and maltodextrin.

In another embodiment, polyethylene oxide present in the sublingual film ranges about 0% to 20% by weight of the water soluble polymeric components, preferably about 1% to 15% by weight of the water soluble polymeric components and more preferably about 10% to 15% by weight of the water soluble polymeric components.

In a further embodiment, hydroxypropylmethyl cellulose present in the sublingual film ranges about 30% to 90% by weight of the water soluble polymeric components, preferably about 40% to 90% by weight of polymeric components, and more preferably about 70% to 85% by weight of the water soluble polymeric components.

In another embodiment, maltodextrin present in the sublingual film ranges about 0% to 60% by weight of water soluble polymeric components, preferably about 1% to 30% by weight of water soluble polymeric components and more preferably about5% to 15% by weight of the water soluble polymeric components.

In a further aspect, the present invention provides a pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Salbutamol dosage with a diffusion flux about17-330?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

In a further aspect, the present invention provides a pharmaceutical sublingual film of Salbutamol delivering target flux amounts for quick relief to the patients with dosage amount as low as 0.5mg/unit.

In a further aspect, the present invention provides a process for preparation of pharmaceutical sublingual film of Salbutamol comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Salbutamol comprising Salbutamol and water soluble polymeric component to form a slurry;
B. Layering the slurry of step Aon polyethylene sheet and
C. Drying the layered composition of step Bat 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.

BRIEF DESCRIPTION OF THE DRAWINGS

A complete understanding of the system and method of the present invention may be obtained by reference to the following drawings:

Fig.1 Elucidates the diffusion of Salbutamol sublingual film through porcine membrane from compositions given in examples 4, 5 and 6 and the orally dissolving tablet composition disclosed in example-7.

Fig.2 Elucidates the in-vitro dissolution of Salbutamol sublingual film composition mentioned inexample 12 as perthe process described in example16.

Fig.3Elucidatesthe diffusion of Salbutamol sublingual film through porcine membrane from compositions given in examples 12, 13, 14 and 15 as disclosed in Example-17.

Fig.4 Elucidates comparative diffusion of Salbutamol from Salbutamol sublingual films through porcine membrane (biological membrane) and synthetic membrane (cellulose acetate membrane) as disclosed in Example-17.

DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention.

As used herein the “water soluble polymeric components” refers to polymeric components at least partially soluble in water or fully or predominantly soluble in water or swellable in water.

The present invention provides the formulation of pharmaceutical sublingual films of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about3-80µg/cm2/min. In embodiments of the present invention, the diffusion flux of the Salbutamol sublingual films also ranged between 5 and 50µg/cm2/min.

The recommended dosage unit of the inventive composition is composed of about0.5 to 4mg of Salbutamol, preferably Salbutamol sulphate.

In embodiments of the present invention, the recommended dosage unit of the inventive composition is composed of 0.5, 1, 2, & 4mg of Salbutamol mixed with the pharmaceutically acceptable excipients.

In embodiments of the present invention the diffusion flux of 0.5mg Salbutamol sublingual film ranges about3-9µg/cm2/min, 2mg Salbutamol sublingual film ranges about18-35µg/cm2/min and 4mg Salbutamol sublingual film ranges about40-75µg/cm2/min.

The present invention further provides a pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Salbutamol dosage with a diffusion flux about17-330?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

The present invention also provides a pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Salbutamol dosage with a diffusion flux about35-410?g/cm2 within ten minutes through the biological mucosal membranes equivalent to human oral mucosa.

In another embodiment of the present invention, the formulation of pharmaceutical sublingual films of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients deliver a diffusion flux ranging between 80and 460µg/cm2/min within ten minutes through the biological mucosal membranes equivalent to human oral mucosa.

The present invention further provides a pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and water soluble polymeric components.

The “water soluble polymer” may be partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer includes but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. In the embodiments of the invention the most preferred water soluble polymers are cellulosic polymers, maltodextrin and polyethylene oxide or combinations thereof. The cellulosic polymers used in combination with polyethylene oxide and maltodextrin are selected from but are not limited to hydroxy propyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC). The polyethylene oxide polymer in combination with a hydrophilic cellulosic polymer and maltodextrin achieves muco-adhesive, flexible, strong films. In accordance with the present invention “water soluble polymeric components” desirably ranges about 5% to 80%w/w of the total weight of pharmaceutical sublingual film of Salbutamol, preferably about20% to 80%w/w of the total weight of pharmaceutical sublingual film of Salbutamol and more preferably about25% to 70% w/w of the total weight of pharmaceutical sublingual film.

In a further embodiment, hydroxypropylmethyl cellulose present in the sublingual film ranges about 30% to 90% by weight of the water soluble polymeric components, preferably about 40% to 90% by weight of polymeric components, and more preferably about 60% to 80% by weight of the water soluble polymeric components.

In another embodiment, maltodextrin present in the sublingual film ranges about 0% to 60% by weight of water soluble polymeric components, preferably about 1% to 30% by weight of water soluble polymeric components and more preferably about 5% to 15% by weight of the water soluble polymeric components.

In another embodiment, polyethylene oxide present in the sublingual film ranges about 0% to 50% by weight of the water soluble polymeric components, preferably about 1% to 30% by weight of the water soluble polymeric components and more preferably about 5% to 15% by weight of the water soluble polymeric components.

A particular embodiment of the invention incorporates a plasticizer to impart flexibility, enhance elasticity and decrease brittleness. Preferred plasticizers include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutylsebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof. In accordance with the present invention plasticizer desirably ranges about 0% to 20% w/w of the total sublingual film, preferably about3% to 15% w/w of the total sublingual film and more preferably about5% to 15% w/w of the total sublingual film.

Another embodiment of the invention incorporates muco-adhesive polymer for adhesion to mucosal membranes in-vivo/in-vitro, wherein the muco-adhesive polymer is chitosan, hyaluronate, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L-lysine), poly(ethylene imine), poly(ethylene oxide), poly, (2-hydroxyethyl methacrylate) and salts, derivatives or copolymers thereof.

The pharmaceutical sublingual film incorporates at least one flavour, chosen from natural and synthetic flavouring liquids. An illustrative list of such agents includes volatile oils, synthetic flavour oils, flavouring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavours.

The pharmaceutical sublingual film incorporates at least one sweetener, chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.

The pharmaceutical sublingual film incorporates at least one diluent which is selected from but not limited to mannitol, microcrystalline cellulose (MCC), lactose, and combinations thereof. In one particular embodiment mannitol was used.

The formulation incorporates mucoadhesive polymer for adhesion to mucosal membranes in-vivo/in-vitro, wherein the mucoadhesive polymer is chitosan, hyaluronate, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L-lysine), poly(ethylene imine), poly(ethylene oxide), poly(2-hydroxyethyl methacrylate) and salts, derivatives or copolymers thereof.

The pharmaceutical sublingual film incorporates at least one surfactant and or non ionicsolubilizer chosen from the following but not limited to poloxamer, polyoxylhydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glycerylpolyglyceryl esters, polyglyceryl esters, glycocholatesand combinations thereof.

The formulation incorporates at least one opacifying agent chosen from the following but not limited to titanium dioxide, colloidal kaolins, aluminium oxide, calcium salts, cetopropyl alcohols, glycerly stearates, propyleneglycol stearates or other opacifyers.

The pharmaceutical sublingual film incorporates at least one colouring agent, which may be provided in a dosage form of the present invention, including pharmaceutically acceptable natural or artificially synthesized dyes. A great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbomedicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin/CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, titanium dioxide, turmeric, natural colors, aronia/redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow and tartrazine.

The present invention provides a process for preparation of pharmaceutical sublingual film of Salbutamol comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Salbutamol comprising Salbutamol and water soluble polymeric components to form a slurry;
B. Layering the slurry of step A on polyethylene sheet and
C. Drying the layered composition of step B at 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.

The process for the preparation of the sublingual film uses a solvent, which may be selected from C2-C4 alcohols selected from ethyl alcohol, isopropyl alcohol, purified water and combinations thereof. In a particular embodiment, purified water was used.

The present invention also provides the pharmaceutical sublingual film of Salbutamol which has the thickness about 0.05mm (50µm) to about 0.2mm (200µm), resulting in weight in the range of about20mg to 80mg, and providing a quick relieving delivery form to the asthmatic patients.

The pharmaceutical sublingual film according to the present invention may have any shape but not limited to circular, square, rectangular or triangular.

The following examples illustrate few methods of preparing pharmaceutical sublingual films in accordance with certain non-limiting aspects of the invention. All percentages in the examples are by weight unless otherwise indicated.

Examples-1, 2 & 3:-
Sublingual films of Salbutamol -4mg, 2mg &0.5mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,1 Eg.,2 Eg.,3
4mg 2mg 0.5mg
Salbutamol Sulphate 11.2% 10.95% 2.74%
Maltodextrin 8-10% 8-12% 8-15%
Polyethylene Oxide 6-8% 6-9% 6-9%
Sucralose 6-8% 7-10% 6-9%
Sodium glycocholate - 3-7% -
Mannitol 4-6% - 5-7%
Hydroxypropylmethyl cellulose 35-50% 35-50% 35-50%
Polyethylene Glycol 9-15% 9-15% -
Glycerol - - 10-20%
Pepper Mint Supreme 1.5-3.5% 1.5-3.5% 1.0-2.0%
Purified water q.s q.s q.s

Examples- 4, 5 & 6
Sublingual films of Salbutamol -4mg, 2mg &0.5mg
Composition:-
Ingredients mg/Sublingual film
Eg.,4 Eg.,5 Eg.,6
4mg 2mg 0.5mg
Salbutamol sulphate 4.8 2.4 0.6
Maltodextrin 4.2 4.2 2.4
Polyethylene Oxide 3 3.4 3.5
Sucralose 3 3 2
Mannitol 3 4 2
Hydroxypropylmethyl cellulose 18 20 10
Polyethylene Glycol 5 4 2
Pepper Mint Supreme 1 1 0.5
Purified water q.s q.s q.s
Total Weight 42mg 42mg 23mg

Process for Preparation:-
1. Dispersion of Salbutamol in purified water.
2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes.
3. Addition of Polyethylene oxide to step 2 and stirring for 3-5 minutes.
4. Addition of Sucralose to step 3 and stirring for 3-5 minutes.
5. Addition of Mannitol to step 4 and stirring for 3-5 minutes.
6. Addition of Hydroxypropylmethyl cellulose, polyethylene glycol and peppermint supreme to step 5 and stirring for 5-10 minutes to form slurry.
7. The slurry of step 6 was layered on polyethylene sheet and dried for 10-20 minutes at 90°C to obtain the sublingual films.

Example 7:ex-vivo/in-vitropermeation studies on Salbutamol sublingual films prepared from composition mentioned in examples 4, 5 & 6 in comparison to Salbutamol sulphate API solution.

Method:-Fresh porcine oral mucosa or synthetic (cellulose acetate) membranes were used to perform the ex-vivo/in-vitro permeability studies. The membrane was inserted between the donor and receptor compartment of Franz diffusion cell (fabricated with a surface permeation area of 1.76cm2 and total permeation area of 26.15cm2). The receptor compartment was filled with phosphate buffer (pH 7.3) and maintained at 37°C ± 0.2°C and the hydrodynamics were maintained by stirring with a magnetic bead at about 50 rpm. One previously weighed sublingual film was placed in intimate contact with the surface of the membrane that was previously moistened with a few drops of simulated saliva. The donor compartment was filled with 1mL of simulated saliva of pH 6.8. Test samples were withdrawn at suitable intervals, replacing the same amount with the fresh medium. The percentage of drug permeated was determined by measuring the absorbance at 276nm using UV-Spectrophotometry. The ex-vivo permeation experiments were conducted in triplicate and the mean values are reported.

The ex-vivo permeation results of Salbutamol sublingual films as prepared from compositions in examples 4, 5 & 6 is provided below.

Salbutamol permeation through porcine membrane
Composition Cumulative Flux(µg/cm2)
at diffusion period of 10 min
Salbutamol Sublingual film- 0.5mg 84
Salbutamol Sublingual film- 2mg 336
Salbutamol Sublingual film- 4mg 459
Salbutamol sulphate API- 4mg 193

As elucidated in Fig.1, ex-vivo permeation of Salbutamol composition (Sublingual film)resulted in cumulative flux ranging from 84 to 459µg/cm2 for 0.5mg, 2mg and 4mg salbutamol sulphate sublingual films in comparison to 193µg/cm2 recorded for Salbutamol sulphate API solution at a diffusion period of 10 minutes.

Examples-8, 9, 10& 11:
Sublingual films of Salbutamol -4mg, 2mg, 1mg& 0.5mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,8 Eg.,9 Eg.,10 Eg.,11
4mg 2mg 1mg 0.5mg
Salbutamol sulphate 15.5% 7.8% 3.9% 1.9%
Maltodextrin 3-10% 3-11% 5-12% 6-11%
Polyethylene Oxide 2-8% 1-6% 2-7% 2-6%
Sucralose 0.5-4% 1-5% 1-4% 2-6%
Mannitol 0.5-3% - - 1-4%
Polyhydroxylated castor oil - - 6-13% 8-20%
Hydroxypropylmethyl cellulose 25-50% 25-45% 25-52% 23-52%
Polyethylene Glycol 10-25% 15-23% 15-22% -
Glycerol - - 10-20% 8-10%
Titanium dioxide - 2-7% - -
Pepper Mint Supreme 0.3-4% 0.3-3% 0.4-2% -
Vanilla flavour - - - 2-6%
Purified water q.s q.s q.s q.s

Examples- 12, 13, 14 & 15:
Sublingual film of Salbutamol -4mg, 2mg, 1mg&0.5mg
Composition:-
Ingredients mg/Sublingual film
Eg.,12 Eg.,13 Eg.,14 Eg., 15
4mg 2mg 1mg 0.5mg
Salbutamolsulphate 4.8 2.4 1.2 0.6
Maltodextrin 2.5 3 2 2.4
Polyethylene Oxide 1.8 2 2 2
Sucralose 0.8 2 3 2
Polyhydroxylated castor oil 4 5 5 5
Hydroxypropylmethyl cellulose 10.9 13.5 14.2 16
Glycerol 4 2 3 2.5
Pepper Mint Supreme 0.7 1 0.5 0.4
Titanium dioxide 1.50 0.1 0.1 0.1
Purified water q.s q.s q.s q.s
Total Weight 31mg 31mg 31mg 31mg

Process for Preparation:-
1. Dispersion of Salbutamol in purified water.
2. Addition of Maltodextrin to step 1 and stirring for 3-5 minutes.
3. Addition of Sucralose to step 2 and stirring for 3-5 minutes.
4. Addition of Polyethylene oxide to step 3 and stirring for 3-5 minutes.
5. Addition of Hydroxypropylmethyl cellulose, glycerol and peppermint supreme to step 4 and stirring for 5-10 minutes.
6. Addition of Polyhydroxylated castor oil to step 5 and stirring for 3-5 minutes.
7. Addition of Titanium dioxide to step 6 and stirring for 3-5 minutes to form slurry.
8. The slurry of step 7 was layered on polyethylene sheet and dried for 10-20 minutes at 90°C to obtain the sublingual films.

Physical Properties of the Sublingual films of Example-12, 13, 14 & 15

Parameter Eg.,12 Eg.,13 Eg.,14 Eg.,15
Film Weight 31mg ± 3mg 31mg ± 3mg 31mg ± 3mg 31mg ± 3mg
Film Thickness 75µ ± 5µ 75µ ± 5µ 75µ ± 5µ 75µ ± 5µ
Film Folding Endurance >350 folds >350 folds >350 folds >350 folds

Example-16:- In-Vitro Dissolution Study of Salbutamol sublingual film prepared by example 12compared to example 14.

Method: in-vitro dissolution studies were carried out using water or simulated salivary fluid (pH 6.8) as a dissolution medium. Temperature of the dissolution medium was maintained at 37±0.5°C. Samples were withdrawn at required interval, filtered (through 0.45µ) and replaced with equivalent amount of fresh dissolution medium. The samples were suitably diluted and estimated UV-Spectrophotometrically at 276nm. The dissolution experiments were conducted in triplicate and the mean values are reported.

Salbutamol--In-Vitro Dissolution% in Water

Dissolution
Period Salbutamol SF
(4mg)
2 min 96.5
5 min 98.0

Salbutamol --In-Vitro Dissolution% in Salivary Fluid (simulated)

Dissolution
Period Salbutamol SF
(4mg) Salbutamol SF
(1mg)
2 min 97.2 96.9
5 min 98.1 99.5

As elucidated in Fig.2, in-vitro dissolution of Salbutamol composition (Sublingual film) provided complete drug disintegration within 40 seconds and drug release up to 95% within 2 minutes in water and simulated salivary fluids.

Example-17:- ex-vivo/in-vitro Permeation of Salbutamol Sublingual films prepared by Examples 12, 13, 14 and 15.

Method: Fresh porcine oral mucosa or synthetic (cellulose acetate) membranes were used to perform the ex-vivo/in-vitro permeability studies. The membrane was inserted between the donor and receptor compartment of Franz diffusion cell (fabricated with a surface permeation area of 1.76cm2 and total permeation area of 26.15cm2). The receptor compartment was filled with phosphate buffer (pH 7.3) and maintained at 37°C ± 0.2°C and the hydrodynamics were maintained by stirring with a magnetic bead at about 50 rpm. One previously weighed sublingual film was placed in intimate contact with the surface of the membrane that was previously moistened with a few drops of simulated saliva. The donor compartment was filled with 1mL of simulated saliva of pH 6.8. Test samples were withdrawn at suitable intervals, replacing the same amount with the fresh medium. The percentage of drug permeated was determined by measuring the absorbance at 276nm using UV-Spectrophotometry. The ex-vivo/in-vitro permeation experiments were conducted in triplicate and the mean values are reported.

Salbutamol Sublingual Film:
Salbutamol permeation through porcine membrane at various diffusion periods
Strength Diffusion
Period Permeation %
Cumulative Flux
(?g/cm2) ‘J’
(?g/cm2/min)
0.25mg 2 min 2.8 3.5 1.75
5 min 6.0 7.4 1.48
10 min 8.9 11.0 1.1
0.5mg 2 min 2.8 6.9 3.45
5 min 6.9 17.1 3.42
10 min 14.5 36.0 3.6
1mg 2 min 4.0 19.9 9.95
5 min 9.0 44.7 8.94
10 min 9.6 47.6 4.76
2mg 2 min 5.7 56.6 28.3
5 min 12.2 121.1 24.22
10 min 18.8 186.6 18.66
4mg 2 min 7.4 146.9 73.45
5 min 16.6 329.6 65.92
10 min 20.6 409.0 40.9

As elucidated in Fig.3, the ex-vivo permeability studies at various time intervals conducted on the sublingual films employing fresh porcine oro-mucosa demonstrated a Salbutamol cumulative flux (µg/cm2) between 3 and 147µg/cm2 after 2 minutes of diffusion period for Salbutamol drug dosages ranging from 0.25mg to 4mg per film. The Salbutamol cumulative flux (µg/cm2) ranged between 7 and 330µg/cm2 after 5 minutes of diffusion period for Salbutamol drug dosages ranging from 0.25mg to 4mg per film. When the diffusion period was extended, the Salbutamol cumulative flux (µg/cm2) ranged between 11 and 409µg/cm2 after 10 minutes of diffusion period for Salbutamol drug dosages ranging from 0.25mg to 4mg per film.

Fig. 4 depicts the comparison of cumulative flux (µg/cm2) values obtained through the biological (porcine oral mucosa) and synthetic (cellulose acetate) membranes for Salbutamol sublingual films of varying strengths. The cumulative flux values obtained through cellulose acetate membrane were about 14% higher than those obtained through the biological membrane (porcine membrane)
,CLAIMS:Claims:-

1. The pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 3-80µg/cm2/min.

2. The pharmaceutical sublingual film according to claim 1, wherein said pharmaceutically acceptable excipients comprise water soluble polymeric components.

3. The pharmaceutical sublingual film according to claim 2, wherein said water soluble polymeric components comprise atleast one water soluble polymer selected from maltodextrin, hydroxypropylmethyl cellulose and polyethylene oxide.

4. The pharmaceutical sublingual film according to claim 1, wherein the said active ingredient consists of about0.5mg to 4mg of Salbutamol or pharmaceutically acceptable salts thereof.

5. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 0.5mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux about 3-9µg/cm2/min.

6. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 2mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux about18-35µg/cm2/min.

7. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 4mg of Salbutamol and pharmaceutically acceptable excipients with a diffusion flux about 40-75µg/cm2/min.

8. The pharmaceutical sublingual film of Salbutamol comprising Salbutamol or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Salbutamol dosage with a diffusion flux of about17-330?g/cm2 within five minutes through the biological mucosal membranes equivalent to human oral mucosa.

9. A process for preparation of pharmaceutical sublingual film of Salbutamol comprising the steps of:
a) Preparing a pharmaceutical sublingual film of Salbutamol comprising Salbutamol and water soluble polymeric components to form a slurry;
b) layering the slurry as per step (a) on polyethylene sheet
c) drying the layered composition of step b) at 80ºC-100ºC for 10-20 minutes to obtain the sublingual film.