DESC:FIELD OF THE INVENTION

The present invention relates to sublingual films of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of 9-105µg/cm2/min through biological mucosal membranes equivalent to human oral mucosa.

BACKGROUND OF THE INVENTION

Terbutaline [(RS)-2-(tert-butylamino)-1-(3, 5-dihydroxyphenyl) ethanol] is used as a bronchodilating agent in the adjunctive therapy of cardiopulmonary diseases. Terbutaline is specifically used as a specific ß2-agonist, mostly affecting the smooth muscles, skeletal muscles and a-adrenergic receptors. Administration of the drug mostly results in bronchodilatation, vasodilatation, and the relaxation of the uterine muscles. The drug is administered for the treatment of bronchial asthma, chronic bronchitis, emphysema, and indicated for the prevention of the preterm labor in pregnancy.

The preferred route of absorption for Terbutaline sulphate is mucosal, trans-mucosal and sublingual.

In the mucosal and tans-mucosal routes, the Terbutaline sulphate is absorbed (33-50%) from the gastrointestinal (GI) tract and around 60% of the absorbed portion is metabolized by the liver under the first pass effect. The drug’s bioavailability is hence decreased by about 15% due to the first pass effect.

For transdermal route, SriniTenjarla et al., reported on the pre-formulation studies and limitations of in-vitro predictive parameters for the trans-dermal delivery of Terbutaline to prevent nocturnal wheezing by providing prolonged duration of action. The required drug flux through the human skin to attain therapeutic concentrations in the blood was calculated to be 3.3 ?g/h for a 10cm2 trans-dermal delivery system. The Terbutaline flux values through the rabbit and guinea-pig skin were 8.3 and 7.7 ?g/cm2/h, respectively. The flux through human full-thickness skin and human epidermis were 0-6 and 3.6 ?g/cm2/h, respectively. [J Pharmacy & Pharmacology 48(11): 1138-1142 (1996)]

Similarly, for trans-dermal route Lalitendu Panigrahi et al., have worked on the effect of pH and organic ester penetration enhancers on skin permeation of Terbutaline sulphate using pseudo-latex type trans-dermal delivery systems. To achieve an effective plasma concentration of Terbutaline sulphate (7 ng/mL), the required permeation rate through the skin was calculated to be 61.6?g/cm2/hour [AAPS PharmSciTech; 6(2):167-173, (2005)].

Several alternate routes have been pursued to avoid the disadvantages of oral formulations such as the first pass effect and the enzymatic degradation within the GI tract.

Preferred alternate route is sublingual. Sublingual administration of the drug means placement of the drug under the tongue and drug reaches directly into the blood stream through ventral surface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and brachiocephalic vein and then drained in to systemic circulation.

The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses 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. The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route and for these formulations, the small volume of saliva is usually sufficient to result in full disintegration of the dosage form in the oral cavity. Sublingual absorption is mostly rapid in action, but also short acting in duration.

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.

Various types of sublingual dosage forms like tablets, sprays and films were developed to overcome the dysphagia, a symptom commonly associated with bronchial asthma, chronic bronchitis etc.

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.

Terbutaline drug in preferred low dosage can be delivered in a quick disintegrating sublingual 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.

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

The main object of the invention relates to formulation of sublingual film of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 9-105?g/cm2/min.

Yet another object of the invention relates to pharmaceutical sublingual films of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and water soluble polymeric components.
Yet another object of the invention is to provide a pharmaceutical sublingual film of Terbutaline delivering high target flux for quick relief to the patients with dosage amount as low as 1mg/unit in an effective and convenient sublingual delivery form compared to the Terbutaline oral tablet forms requiring a higher dosage of 5mg/unit.

Yet another object of the invention is to provide a pharmaceutical sublingual film of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof, surfactant/non-ionic solubilizers and at least one pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides formulation and method of preparation of pharmaceutical sublingual films of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients with a diffusion flux of about 9-105?g/cm2/min.

In one embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Terbutaline comprising 5mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux of about 45-105µg/cm2/min.

In an another embodiment of the invention, the present invention provides a pharmaceutical sublingual film of Terbutaline comprising 2.5mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux of about 20-70 µg/cm2/min.

In further embodiments of the invention, the present invention provides a pharmaceutical sublingual film of Terbutaline comprising 1mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux of about 10-17 µg/cm2/min.

In another aspect, the present invention provides a pharmaceutical sublingual film of Terbutaline comprising Terbutaline 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 Terbutaline, preferably about 35% to 75% w/w of the total weight of pharmaceutical sublingual film of Terbutaline and more preferably about 40% to 70% w/w of the total weight of pharmaceutical sublingual film.

In preferred embodiments, the water soluble polymeric component 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 Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Terbutaline dosage with a diffusion flux about 50-370?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 Terbutaline delivering target flux amounts for quick relief to the patients with dosage amount as low as 1mg/unit.

In a further aspect, the present invention provides a process for preparation of pharmaceutical sublingual film of Terbutaline comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Terbutaline comprising Terbutaline sulphate and water soluble polymeric component 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.

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 terbutaline sublingual film through porcine membrane from compositions given in examples 4, 5 and 6 as disclosed in example-7 and in comparison with the Terbutaline API.

Fig.2 Elucidates the in-vitro dissolution of Terbutaline sulphate sublingual film composition mentioned in example 11 as per the process described in example 14.

Fig.3 Elucidates the diffusion of terbutaline sublingual film through porcine membrane from compositions given in examples 11, 12 and 13 as disclosed in Example-15.

Fig.4 Elucidates the permeation enhancement of terbutaline in sublingual films diffused through porcine membrane by incorporating various permeation enhancers.

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 Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 9-105µg/cm2/min. In embodiments of the present invention, the diffusion flux of the Terbutaline sublingual films also ranged between 13 and 46µg/cm2/min.

The recommended dosage unit of the inventive composition is composed of about1mg to 5mg of Terbutaline, preferably Terbutaline sulphate.

In embodiments of the present invention, the recommended dosage unit of the inventive composition is composed of 1, 2.5 & 5mg of Terbutaline sulphate mixed with the pharmaceutically acceptable excipients.

In embodiments of the present invention the diffusion flux of 1mg Terbutaline sulphate sublingual film ranges about 10-17µg/cm2/min, 2.5mg Terbutaline sulphate sublingual film ranges about 20-70µg/cm2/min and 5mg Terbutaline sulphate sublingual film ranges about 45-105µg/cm2/min.

The present invention further provides a pharmaceutical sublingual film of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Terbutaline dosage with a diffusion flux about 50-370?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 Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Terbutaline dosage with a diffusion flux about 99-517?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 Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients deliver a diffusion flux ranging between 133 and 463µg/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 terbutaline comprising terbutaline 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, locust 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 75%w/w of the total weight of pharmaceutical sublingual film of Terbutaline, preferably about 35% to 75%w/w of the total weight of pharmaceutical sublingual film of Terbutaline and more preferably about 40% 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 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 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 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.

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 about 2% to 15% w/w of the total sublingual film and more preferably about 3% to 12% 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 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 opacifiers.

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, carbo medicinalis, 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 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 pharmaceutical sublingual film incorporates at least one surfactant/non ionic solubilizer chosen from the following but not limited to poloxamer, polyoxyl hydrogenated castor oil, glyceryl polyethylene glycol oxystearates, fatty acid glycerylpolyglyceryl esters, polyglyceryl esters, and combinations thereof.

The present invention provides a process for preparation of pharmaceutical sublingual film of Terbutaline comprising the steps of:
A. Preparing a pharmaceutical sublingual film of Terbutaline comprising Terbutaline sulphate 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 Terbutaline sulphate which has the thickness about 0.06mm (60µm) to about 0.2mm (200µm), resulting in weight in the range of about 20mg to 100mg, and useful as a bronchodilator.

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 Terbutaline sulphate- 5mg, 2.5mg & 1mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,1 Eg.,2 Eg.,3
5mg 2.5mg 1mg
Terbutaline sulphate 11.63% 11.63% 4.65%
Maltodextrin 8-11% 8-12% 7-13%
Polyethylene Oxide 6-8% 5-9% 5-9%
Polyoxyl hydroxystearate
(Kolliphor) 10-12% - -
Sucralose 6-9% 6-10% 6-10%
Locust bean gum - - 1-4%
Mannitol 3-8% 3-6% 9-12%
Hydroxypropylmethyl cellulose 35-50% 35-50% 35-50%
Polyethylene Glycol 400 9-13% - 7-10%
Glycerol - 10-15% 9-14%
Pepper Mint Supreme 1.5-4% - 1.5-3.5%
Lemon Lime Royal - 3-7% -
Purified water q.s q.s q.s

Examples- 4, 5 & 6:-
Sublingual films of Terbutaline sulphate- 5mg, 2.5mg & 1mg
Composition:-
Ingredients mg/Sublingual film
Eg.,4 Eg.,5 Eg.,6
5mg 2.5mg 1mg
Terbutaline sulphate 5 2.5 1
Maltodextrin 4 2 2
Polyethylene Oxide 3 2 1.5
Sucralose 3 2 2
Mannitol 3 1 2.5
Hydroxypropylmethyl cellulose 19 9.5 10
Polyethylene Glycol 5 2 2
Pepper Mint Supreme 1 0.5 0.5
Purified water q.s q.s q.s
Total Weight 43mg 21.5mg 21.5mg

Process for Preparation:-
1. Dispersion of Terbutaline sulphate 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 Hydroxypropylmethylcellulose, 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-Vitro Permeation studies on Terbutaline sublingual films prepared from composition mentioned in examples 4, 5 & 6.

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 1 mL 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 280nm using UV-Spectrophotometry. The ex-vivo permeation experiments were conducted in triplicate and the mean values are reported.

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

Terbutaline permeation through porcine membrane
Composition Cumulative Flux(µg/cm2)
at diffusion period of 10 min
Terbutaline Sublingual film- 1mg 133
Terbutaline Sublingual film- 2.5mg 316
Terbutaline Sublingual film- 5mg 463
Terbutaline API- 5mg 184

Examples-8, 9 & 10:
Sublingual films of Terbutaline sulphate- 5mg, 2.5mg & 1mg
Composition:-
Ingredients Percentage range Per Unit
Eg.,8 Eg.,9 Eg.,10
5mg 2.5mg 1mg
Terbutaline sulphate 5mg 2.5mg 1mg
Maltodextrin 4-10% 4-10% 5-9%
Polyethylene Oxide 3-8% 3-7% 4-9%
Sucralose 1-5% 1-5% 3-5%
Mannitol 1-4% - 1-5%
Polyoxyl castor oil 10-15% - -
Hydroxypropylmethyl cellulose 25-50% 25-50% 35-50%
Titanium dioxide - 3-8% -
Polyethylene Glycol 9-20% - 4-8%
Glycerol - 10-25% 10-20%
Pepper Mint Supreme 1.5-4% - -
Lemon Lime Royal - 3-7% -
Vanilla Flavour - - 2-8%
Purified water q.s q.s q.s

Examples- 11, 12& 13:
Sublingual film of Terbutalinesulphate-5mg, 2.5mg & 1mg
Composition:-
S.No Ingredients mg/Sublingual film
Eg.,11 Eg.,12 Eg.,13
5mg 2.5mg 1mg
1. Terbutaline sulphate 5 2.5 1
2. Maltodextrin 2 3 2
3. Polyethylene Oxide 2 2 2
4. Sucralose 0.9 2.5 3
5. Polyoxyl castor oil 4 5 4
6. Hydroxypropylmethyl cellulose 9.9 11.9 14.4
7. Glycerol 4 2 3
8. Pepper Mint Supreme 0.7 1 0.5
9. Titanium dioxide 1.50 0.1 0.1
10. Purified water q.s q.s q.s
Total Weight 30 30 30

Process for Preparation:-
1. Dispersion of Terbutaline sulphate 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 Polyoxyl 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-11, 12, & 13

Parameter Eg.,11 Eg.,12 Eg.,13
Film Weight 30mg ± 5mg 30mg ± 5mg 30mg ± 5mg
Film Thickness 75µ ± 5µ 75µ ± 5µ 75µ ± 5µ
Film Folding Endurance >300 folds >300 folds >300 folds

Example-14:- In-Vitro Dissolution Study of Terbutaline sublingual films prepared by examples 11, 12 and 13

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 280nm. The dissolution experiments were conducted in triplicate and the mean values are reported.

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

Dissolution Period Terbutaline SF
(5mg)
2 min 100
5 min 100

Terbutaline --In-Vitro Dissolution% in Water

Dissolution Period Terbutaline SF
(5mg)
2 min 97.4
5 min 98.3

As elucidated in Fig.2, the in-vitro dissolution of Terbutaline composition (Sublingual film) provided complete drug disintegration within 50 seconds and drug release up to 98% within 2 minutes in water and simulated salivary fluids.

Example-15:- Ex-Vivo Permeation of Terbutaline Sublingual films prepared by Examples 11, 12 and 13.

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 1 mL 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 280nm using UV-Spectrophotometry. The ex-vivo permeation experiments were conducted in triplicate and the mean values are reported.

Terbutaline Sublingual Film:
Terbutaline permeation through porcine membrane at various diffusion periods
Strength Diffusion
Period Permeation %
Cumulative Flux
(?g/cm2) ‘J’
(?g/cm2/min)
Terbutaline Sublingual film
5mg 2 min 7.41 209 104.5
5 min 12.93 365 73
10 min 18.27 517 51.7
2.5mg 2 min 9.6 136 68
5 min 9.9 140 28
10 min 15.1 214 21.4
1mg 2 min 5.8 33 16.5
5 min 8.8 50 10
10 min 17.4 99 9.9

As elucidated in Fig.3, Terbutaline cumulative flux (µg/cm2) at various strengths ranging from 1 to 5mg was recorded after 2, 5 and 10 minutes through porcine membrane.

The ex-vivo permeability studies at various time intervals conducted on the sublingual films employing fresh porcine oro-mucosa demonstrated a Terbutaline cumulative flux (µg/cm2) between 30 and 210 µg/cm2 after 2 minutes of diffusion period for Terbutaline drug dosages ranging from 1mg to 5mg per film. The Terbutaline cumulative flux (µg/cm2) ranged between 50 and 365µg/cm2 after 5 minutes of diffusion period for Terbutaline drug dosages ranging from 1mg to 5mg per film. When the diffusion period was extended, the Terbutaline cumulative flux (µg/cm2) ranged between 99 and 520 µg/cm2 after 10 minutes of diffusion period for Terbutaline drug dosages ranging from 1mg to 5mg per film.

Fig.4 Elucidates the permeation enhancement of terbutaline in sublingual films diffused through porcine membrane by incorporating various permeation enhancers. The terbutaline flux (µg/cm2/min) increased up to 34% by incorporating Kolliphor in to the sublingual film formulation. Incorporation of permeation enhancers, viz., Transcutol and Sodium glycocholate also resulted in permeation enhancement with the increase in terbutaline flux up to 21% and 26%, respectively compared to the formulation without permeation enhancers.

,CLAIMS:1. The pharmaceutical sublingual film of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients with a diffusion flux of about 9-105µg/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 at least 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 about 1 to 5 mg of terbutaline or pharmaceutically acceptable salts thereof.

5. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 1mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux about 10-17µg/cm2/min.

6. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 2.5mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux about 20-70µg/cm2/min.

7. The pharmaceutical sublingual film according to claim 1, wherein the sublingual film consists of 5mg of Terbutaline sulphate and pharmaceutically acceptable excipients with a diffusion flux about 45-105µg/cm2/min.

8. The pharmaceutical sublingual film of Terbutaline comprising Terbutaline or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable excipients delivering Terbutaline dosage with a diffusion flux of about 50-370?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 Terbutaline comprising the steps of:
a) Preparing a pharmaceutical sublingual film of Terbutaline comprising Terbutaline sulphate 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.