DESC:TECHNICAL FIELD OF THE INVENTION:
The present invention relates to rapidly disintegrating oral dosage forms and to a process for preparation comprising an open matrix network carrying the pharmaceutically active substance, a water soluble or water dispersible carrier material and discrete units of the suspension or emulsion in form of liquid units contained in pockets of suitable mould, solid units such as frozen units, gelled units or frozen discrete units dried by freeze drying.

BACKGROUND AND PRIOR ART OF THE INVENTION:
US 4,642,903 disclose freeze-drying a dispersion to form a freeze-dried foam containing said active ingredient.

US 5,188,825 discloses freeze-drying solid dosage form comprising freeze drying aqueous suspension comprising water insoluble active ingredient bound to an ion exchange resin and an aqueous carrier agent consisting essentially of water and a bulk-forming agent selected from the group consisting of gelatin, polyvinylpyrrolidone, polyethylene glycol, polysaccharides, and combinations thereof.

US 5,631,023 discloses a freeze-dosage form comprising solvent, gelatin, therapeutic agent having a particle size ranging from about 1 to about 400 microns and xanthum gum.

US 5,738,875 discloses a composition and process for the preparation of Imodium Quick-Dissolve® tablets.

US 5,827,541 discloses a freeze-dosage form comprising solvent, surfactant, hydrophobic therapeutic agent and water-soluble or water-dispersible carrier.

US 5,976,577 and US 6,413,549 discloses a freeze-dried dosage form comprising forming a suspension in a continuous phase of coarse particles of active substance in a carrier material being selected from the group consisting of water-soluble and water-dispersible carrier materials (Gelatin).

US 6,709,669 discloses a process for preparing a pharmaceutical composition in a fast-dispersing dosage form having an active ingredient and fish gelatin carrier comprising a step of forming a network of the active ingredient and non-gelling fish gelatin carrier by subliming solvent from an admixture in the solid state in which the admixture comprises the active ingredient, the carrier and a solvent for the carrier.

US 9,192,580 discloses a pharmaceutical composition in an oral solid molded fast-dispersing dosage form comprising an active ingredient and a non-hydrolyzed, non-gelling fish gelatin carrier which releases the active ingredient, wherein said composition disintegrates within 1 to 60 seconds of being placed in contact with fluid, and wherein said dosage form comprises a network of the active ingredient and the non-hydrolyzed, non-gelling fish gelatin carrier prepared by the process of subliming solvent from an admixture in the solid state in which the admixture comprises the active ingredient, the non-hydrolyzed, non-gelling fish gelatin carrier and a solvent.

SUMMARY OF THE INVENTION
Having felt the need for a specifically described and demonstrated process and compositions, the present inventors have come up with a detailed process and specific compositions for rapidly disintegrating dosage forms, prepared by a process of lyophilisation, wherein the frozen discrete units are obtained by freeze drying in filled blisters and packed in aseptic conditions.

In an aspect, the present invention provides a lyophilized rapidly disintegrating solid oral dosage form composition comprising a pharmaceutically active substance with matrix forming agent(s) or binding agent(s), structure forming agent(s), optionally an oleaginous vehicle/carrier, together with other pharmaceutically acceptable excipients, wherein the suspension or solution or emulsion of said composition filled into the pre-formed blister pockets are freeze dried at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2 followed by lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain the desired product.
The process for preparing a lyophilized rapidly disintegrating solid oral dosage form containing the pharmaceutically active substance, in another aspect of the invention, comprises;
i. preparing a suspension or solution or emulsion comprising pharmaceutically active ingredient, binder(s), matrix forming agent(s), structure forming agent(s), optionally an oleaginous vehicle/ carrier, together with other pharmaceutically acceptable excipients to obtain a homogenous suspension,
ii. transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
iii. freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2, and
iv. lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a rapidly disintegrating solid oral dosage.

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention relates to a process for preparing rapidly disintegrating solid oral dosage form in an open matrix network carrying the pharmaceutically active substance along with pharmaceutically acceptable excipients and carrier solvents such as water with or without co-solvent such as alcohol, wherein the composition filled blisters are directly freeze dried which are sealed to form ready to dispatch packs.

In a preferred embodiment, the present invention relates to a lyophilized rapidly disintegrating solid oral dosage form composition comprising a pharmaceutically active substance with matrix forming agent(s) or binding agent(s), structure forming agent(s), optionally an oleaginous vehicle/carrier, together with other pharmaceutically acceptable excipients, wherein the suspension or solution or emulsion of said composition filled into the pre-formed blister pockets are freeze dried at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2 followed by lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain the desired product.

In another embodiment, the present invention discloses a process for producing a lyophilized rapidly disintegrating solid oral dosage form composition containing the pharmaceutically active substance, the said process comprising;
(i) preparing a suspension or solution or emulsion containing pharmaceutically active substance, binder(s), matrix forming agent(s), structure forming agent(s), optionally an oleaginous vehicle/carrier together with other pharmaceutically acceptable excipients to obtain a homogenous suspension,
(ii) transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
(iii) freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2, and
(iv) lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a lyophilized rapidly disintegrating solid oral dosage.

Accordingly, the present invention provides a composition of lyophilized, rapidly disintegrating solid oral dosage forms the said composition comprising a pharmaceutically active substance with matrix forming agent(s) or binding agent(s), structure forming agent(s), optionally an oleaginous carrier/vehicle, along with other pharmaceutically acceptable excipients.

The matrix forming or binding agent(s) is selected from the group consisting of sodium alginate, pullulan or hypromellose or mixtures thereof. The oleaginous carrier/vehicle is selected from the group consisting of olive oil, sesame oil, castor oil, coconut oil or corn oil or mixtures thereof. The structure forming agent(s) is selected from the group consisting of maltodextrin or mannitol or mixtures thereof.

In an embodiment, the present invention discloses a process for producing a lyophilized rapidly disintegrating solid oral dosage form containing the pharmaceutically active substance, said process comprising;
(i) preparing a suspension or solution or emulsion containing pharmaceutically active substance, with an oleaginous vehicle/carrier, hypromellose as matrix forming agent, binder(s), structure forming agent(s) together with pharmaceutically acceptable ingredients to obtain an homogenous suspension,
(ii) transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
(iii) freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2,
(iv) lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a rapidly disintegrating solid oral dosage.

In accordance with the aforesaid embodiment, the present invention discloses a composition of a lyophilized rapidly disintegrating solid oral dosage form in an oil in water emulsion, the said composition comprising pharmaceutically active substance with a oleaginous vehicle selected from the group consisting of olive oil, sesame oil, castor oil, coconut oil, corn oil, along with pharmaceutically acceptable excipients selected from the group comprising polysorbate 80 as emulsifying agent, Hypromellose as a matrix forming agent or binding agent and maltodextrin as structure forming agent.

The present composition of lyophilized rapidly disintegrating solid oral dosage form comprises the active ingredient in concentrations ranging from 2% to 6% by weight of the composition, binding agent in concentrations ranging from 0.20% to 12% by weight of the composition, an oleaginous carrier/vehicle in concentrations ranging from 2% to 20% by weight of the composition, structure forming agent in concentrations ranging from 2% to 10% by weight of the composition and other pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a process for producing a lyophilized rapidly disintegrating solid oral dosage form containing pharmaceutically active substance, the said process comprising;
(i) preparing a pharmaceutically active substance as an oil in aqueous suspension, adding hypromellose and other pharmaceutically acceptable excipients to obtain an homogenous suspension,
(ii) transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
(iii) freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2,
(iv) lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a lyophilized rapidly disintegrating solid oral dosage form.

In accordance with the aforesaid embodiment, the present invention discloses a composition of lyophilized rapidly disintegrating oral solid dosage form in oil in water emulsion, the said composition comprising pharmaceutically active substance as an oil in an aqueous suspension comprising polysorbate 80 as an emulsifying agent, Hypromellose as matrix forming agent or binding agent and maltodextrin as a structure forming agent.

In yet another embodiment, the present invention relates to a process for producing a lyophilized rapidly disintegrating solid oral dosage form containing pharmaceutically active substance, the said process comprising;
(i) preparing a suspension or solution or emulsion containing pharmaceutically active substance, pullulan as matrix forming agent, binder(s), structure forming agent(s), optionally an oleaginous carrier, along with other pharmaceutically acceptable excipients to obtain an homogenous suspension,
(ii) transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
(iii) freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2,
(iv) lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a rapidly disintegrating solid oral dosage form.

In accordance with the aforesaid embodiment, the present invention provides a lyophilized rapidly disintegrating oral solid dosages form with a composition comprising pullulan as a matrix forming or binding agent, Polysorbate 80 as a dispersing agent and mannitol as a structure forming agent.

In a further embodiment, the present invention discloses a process for producing a lyophilized, rapidly disintegrating solid oral dosage containing pharmaceutically active substance, the said process comprising;
(i) preparing a suspension or solution or emulsion containing pharmaceutically active substance, sodium alginate as matrix forming agent, binder(s), structure forming agent(s), optionally an oleaginous carrier, along with other pharmaceutically acceptable ingredients to obtain an homogenous suspension,
(ii) transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
(iii) freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2,
(iv) lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a rapidly disintegrating solid oral dosage.

The aforesaid process results in the formation of a lyophilized rapidly disintegrating, oral, solid, dosage form composition comprising pharmaceutically active substance, sodium alginate as the matrix forming agent, polysorbate 80 as the dispersing agent and mannitol as the structure forming agent for rapid dispersion.

The discrete units of the suspension or solution or emulsion may be in the form of liquid units, for example contained within the pockets of a suitable mould, solid units, for example frozen units, or gelled units where the carrier material readily forms a gel.

The liquid solution or suspension which may be contained within the pockets of a suitable mould is frozen, for example by passing a gaseous cooling medium, such as liquid nitrogen over the mould, or by inserting the mould into a nitrogen spray freezing chamber, or cooling by passing the mould over a cold surface. After the dosage forms have been frozen, the mould may be stored in a cold store, prior to drying. Frozen discrete units may be dried by freeze drying.

The solid dosage forms are prepared by the sublimation or removal of solvent from a solution or suspension or emulsion comprising the pharmaceutically active substance and the carrier material. Sublimation or removal of solvent is preferably carried out by freeze drying.

The solvent is sublimed in a freeze-drying process under a reduced pressure which transforms the solid solvent directly into a vapour. The freeze-drying process will generally be carried out in a freeze-drying chamber typically operating under a vacuum of 0.1 to 1.0 mBar for a period of time from 100 to 800 minutes.

The process of the present invention is also intended to be applied to pharmaceutically acceptable salt form of the active ingredient or the medicament.
The other excipients such as colorants, sweeteners, flavouring agents, taste-masking agents or preservatives can be added to the aqueous phase of the present composition. The process of taste masking can be carried out by any of the processes known in the art, not limiting to complexation with cyclodextrins, ion exchange resins or any other suitable agents. Taste masking can also be achieved by coating the solid pharmaceutical dosage forms with water soluble or insoluble polymers or polymers having pH dependent solubility or waxes.

The solvent used in forming the solution or suspension of pharmaceutically active substance is preferably water but it may be admixed with co-solvent such as alcohol, if it desired to improve the solubility of active substance.

The specific examples of the compositions and processes thereof are described hereinafter. The following examples given by way of illustration will serve to illustrate the practice of this invention and therefore should not be construed to limit the scope of the invention

Example 1:
Functional category % Composition
Active 4.00
Matrix former (Binder) 0.40 - 6.00
Structure forming agent (Diluent) 2.00 - 10.00
Oleaginous vehicle 2.00 - 20.00
Emulsifying agents 0.05 -1.50
Sweetener 0.20 - 0.60
Flavouring Agent 0.40 - 2.40
Carrier (Vehicle) 90.55 – 49.50
Note - * Water was removed during processing

Manufacturing process:
The ingredients pharmaceutically active substance, structure forming agent such as maltodextrin and/or mannitol; matrix forming agent such as hypromellose; oleaginous vehicle such as olive oil; Emulsifying agents such as polysorbate 80;sweetener such as aspartame and flavour were accurately weighed and dispensed. Oil in water emulsion was prepared using the following procedure.
Step 1: A weighed quantity of purified water was transferred into a glass beaker and the stirrer was placed in the centre of the beaker and stirred at 500 rpm.
Note: Each material from step 2 to step 6 was added under steady stirring maintained between 200 to 800 rpm.
Step 2: Added slowly, the weighed quantity of maltodextrin to step 1 under continuous stirring
Step 3: Added weighed quantity of hypromellose to solution of step 2 and stirred well until a clear solution was obtained.
Step 4: Added weighed quantity of mannitol to solution of step 3 and stirred well until a clear solution was obtained.
Step 5: The weighed quantity of aspartame was added to suspension of step 4 and stirred well until a uniform suspension was obtained.
Step 6: The weighed quantity flavour was added to suspension of step 5 and stirred well until a uniform suspension was obtained.
Step 7: In separate vessel added weighed quantity of pharmaceutically active substance to olive oil and mixed well until a uniform mucilage was obtained.
Step 8: The weighed quantity of polysorbate 80 was added to mucilage of step 7 with continuous stirring
Step 9: The above step 7 mucilage was added drop by drop with continuous mixing to step 6 suspension until to obtain homogenous emulsion.

Filling and loading
Transferred the bulk suspension obtained from step 9 to dosing tank with assembly connected with peristaltic pump and the suspension was kept under stirring at 400 rpm until the end of the filling process.

Quick freezing
Run suspension filled blisters sheets through a liquid nitrogen freezing tunnel with targeted liquid nitrogen tunnel temperature of - 110 ± 40 0C and pressure variations from 5 – 7 Kg/cm2
After loading required quantity of filled blisters, the door of lyophilizer was closed and the product was lyophilized as per the below lyo cycle parameters.

Lyo cycle parameters –
Primary drying temperature - -5 to-35 oC, Secondary dryingtemperature - 20oC to - 40 oC
Unloading: After completion of Lyo cycle, the blisters were unloaded from the lyophilizer carefully.
Sealing: The unloaded blisters were sealed with paper aluminium foil by applying heat range of 180 ± 30oC to meet leak test pass criteria.

Examples as above are not limiting the scope of the invention. The quantities of the ingredients and the process steps thereof may be modified suitably to meet the lyophilizing or freeze drying parameters and the consistency of the final suspension or solution being filled into the blister cavities for freeze drying and sealing.
Examples of Rapidly Disintegrating Tablets of Antihistaminic drugs
Example 2: Rapidly Disintegrating Tablets of Loratadine
S. No. Ingredients % composition
1 Loratadine 4
2 Pullulan 1 - 10
3 Mannitol 1 - 10
4 Citric acid anhydrous 0.02 - 0.5
5 Peppermint flavour 0.1 - 1
6 Purified water 70 - 95
Total 100

Manufacturing process for example 2:

(i) Preparing a suspension comprising Loratadine, binder(s), matrix-forming agent(a) and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -60°C to -120°C and pressure ranging from 3 kg/cm2 to 9 kg/cm2,
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -40°C to 0°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 35°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Loratadine.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 10 seconds (limit NMT 30 seconds). The dissolution release of the samples in SGF without enzyme was found to have 80 Q in 3 to 10 minutes with % RSD NMT 5% and assay 95 -105 %w/w. Related substances were within the limits.

Examples of Rapidly Disintegrating Tablets of Anti-diarrhoeal drugs
Example 3: Rapidly Disintegrating Tablets of Loperamide hydrochloride
S. No. Ingredients % w/w
1 Loperamide hydrochloride 1.33
2 Pullulan 2 - 10
3 Mannitol 1 - 12
4 Sodium bicarbonate 0.1 - 1
5 Aspartame 0.1 - 2
6 Peppermint flavour 0.05 - 0.75
7 Kolliphor 80 0.05 -1
8 Purified water * 40 - 90
Total 100
* - Will not remain in final product, removed during the process

Manufacturing process for example 3:
(i) Preparing a suspension comprising Loperamide, binder(s), matrix-forming agent(a) and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -70°C to -120°C and pressure ranging from 3 kg/cm2 to 8 kg/cm2,
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -50°C to -10°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Loperamide hydrochloride.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 10 seconds (limit NMT 30 seconds). The dissolution release of the samples in 0.01 N HCl was found to have 80 Q in 5 to 10 minutes with % RSD NMT 5% and assay 95 -110 %w/w. Related substances were within the limits

Rapidly Disintegrating Tablets of antiemetics
Example 4: Rapidly Disintegrating Tablets of Ondansetron
S. No. Ingredients % w/w
1 Ondansetron 1.6
2 Pullulan 1 - 10
3 Mannitol 2 - 15
4 Aspartame 0.1 - 2
5 Strawberry flavour 0.05 - 0.75
6 Polysorbate 80 0.05 -1
7 Purified water * 50 - 90
Total 100
* - Will not remain in final product, removed during the process

Manufacturing process for example 4:

(i) Preparing a suspension comprising Ondansetron, binder(s), matrix-forming agent(a) and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -60°C to -120°C and pressure ranging from 3 kg/cm2 to 8 kg/cm2,
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -40°C to 20°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Ondansetron.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 10 seconds (limit NMT 30 seconds). The dissolution release of the samples in 0.1 N HCl was found to have 80 Q in 5 to 10 minutes with % RSD NMT 5% and assay 90 -110 %w/w. Related substances were within the limits.

Example 5: Rapidly Disintegrating Tablets of Cetirizine HCl
S. No. Ingredients % w/w
1 Cetirizine HCl 2
2 Betacyclodextrin 10 - 40
3 Cetirizine HCl + Betacyclodextrin
4 Sodium Bicarbonate 0.1 – 5
5 Pullulan 0.1 – 5
6 Polysorbate 80 0.01 – 2
7 Sucralose 0.01 – 2
8 Mannitol 1 - 20
9 Masking Flavour 0.1 - 10
10 Menthol Micron 0.1 - 10
11 Orange flavour 0.1 - 10
12 Purified water 50 - 70
Total 100
* - Will not remain in final product, removed during the process
Manufacturing process for example 5:

(i) Preparing a suspension comprising Cetirizine HCl, binder(s), matrix-forming agent(a) , complexing agent and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -70°C to -120°C and pressure ranging from 3 kg/cm2 to 8 kg/cm2.
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -50°C to -10°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Ibuprofen.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 30 seconds (limit NMT 30 seconds)

Taste masking of bitter drugs
Example 6: Rapidly Disintegrating Tablets of Dimenhydrinate
S. No. Ingredients % composition
1 Dimenhydrinate 6.25
2 Acesulfame potassium 0.1 – 1.5
3 Aspartame 0.1 - 2
4 Mannitol 1 - 10
5 Indion-204 5 - 15
6 Citric acid anhydrous 0.05 - 1
7 Polysorbate-80 0.05 – 1
8 Pullulan 1 -10
9 Orange flavor 0.1 - 2
10 Purified water * 50 - 85
Total 100
* - Will does not remain in final product, removed during the process

Manufacturing process for example 6:
(i) Preparing a suspension comprising Loperamide, binder(s), matrix-forming agent(s), taste masking agents and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -70°C to -120°C and pressure ranging from 3 kg/cm2 to 9 kg/cm2,
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -45°C to 20°C followed by lyophilizing at a secondary drying temperature ranging from 25°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Dimenhydrinate.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 20 seconds (limit NMT 30 seconds). The dissolution release of the samples in 0.1 N HCl was found to have 75 Q in 15 minutes with % RSD NMT 5% and assay 95 -105 %w/w. Related substances were within limits.

Example 7: Rapidly Disintegrating Tablets of Ibuprofen
S. No. Ingredients % w/w
1 Ibuprofen 25
2 Pullulan 0.5 – 5
3 Mannitol 1-10
4 Fumaric acid 1-5
5 Advantame 0.01 - .1
6 Polysorbate 80 0.05-0.5
7 Menthol 0.5 – 2.5
8 Peppermint flavor 0.5 – 3
9 Purified water * 50-70
Total 100
* - Will does not remain in the final product, removed during the process

The manufacturing process, for example, 7:
(i) Preparing a suspension comprising Ibuprofen, binder(s), matrix-forming agent(a) and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -70°C to -120°C and pressure ranging from 3 kg/cm2 to 8 kg/cm2,
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -50°C to -10°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Ibuprofen.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 30 seconds (limit NMT 30 seconds). The dissolution release of the samples in pH 7.2 phosphate buffer was found to have 80 Q in 30 minutes with % RSD NMT 5% and assay 95 -105 %w/w. Related substances were within limits.

Sublingual Tablets for emergency treatment of allergic reactions (Type I) including anaphylaxis
Example 8: Sublingual Tablets of Epinephrine
S. No. Ingredients % w/w
1 Epinephrine base / Epinephrine bitartrate 4.00
2 Citric acid anhydrous 0.5 – 5
3 Aspartame 0.1 – 5
4 Sodium Metabisulfite 1 – 3
5 Maltodextrin 5 – 15
6 Hydroxypropyl methylcellulose 1 – 5
7 Purified Water IH * 50 – 80
Total 100
* - Will not remain in final product, removed during the process

Manufacturing process for example 8:
(i) Preparing a suspension comprising Epinephrine / Epinephrine bitartrate, binder(s), matrix-forming agent(a), stabilizing agent and pharmaceutically acceptable ingredients to obtain a homogenous suspension,
(ii) Transferring the homogenous suspension to a dosing tank and stirring/homogenizing the said suspension until the end of the filling process,
(iii) Forming blister pockets in blister filling machine. Use of peristaltic pump (or any pump of equivalent performance) to dose accurate amount of suspension into preformed blister pockets,
(iv) Freezing the drug suspension filled blister pockets by passing through liquid nitrogen freezing tunnel temperature ranging from -70°C to -120°C and pressure ranging from 3 kg/cm2 to 8 kg/cm2.
(v) The frozen product is then placed into lyophilizer. Lyophilizing the said frozen blister sheets at a primary drying temperature ranging from -50°C to -10°C followed by lyophilizing at a secondary drying temperature ranging from 15°C to 50°C under specific ranges of vacuum to obtain a rapidly disintegrating solid oral dosage form comprising Ibuprofen.
(vi) The freeze-dried tablets checked for appearance, strength, dispersion and LOD, then analyzed for identification, assay, related substance, dissolution and water content).
(vii) The freeze-dried tablets disintegration resulted in less than 30 seconds (limit NMT 30 seconds).

Example 9
Proteins and peptides orally disintegrating tablets prepared through lyophilized (freeze-dried) technology of the present invention as described above.
Critical excipients – polymers(enteric coating), stabilizers, permeation enhancers and carriers.
,CLAIMS:1. A lyophilized rapidly disintegrating solid oral dosage form composition comprising a pharmaceutically active substance with matrix forming agent(s), binding agent(s), structure forming agent(s), optionally an oleaginous vehicle, together with other pharmaceutically acceptable excipients, wherein the suspension or solution or emulsion of said composition filled into the pre-formed blister pockets are freeze dried at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2followed by lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain the desired lyophilized rapidly disintegrating dosage form.

2. The lyophilized rapidly disintegrating solid oral dosage form composition as claimed in claim 1, wherein, the active ingredient is in the concentration ranging from 2% to 6% by weight of the composition, matrix forming agent(s) or binding agent in concentration ranging from 0.20% to 12% by weight of the composition, an oleaginous vehicle in concentration ranging from 2% to 20% by weight of the composition, structure forming agent in concentrations ranging from 2% to 10% by weight of the composition together with other pharmaceutically acceptable excipients.

3. The lyophilized rapidly disintegrating solid dosage form composition as claimed in claim 1, wherein, the matrix forming agent(s) or binding agent(s) is selected from the group consisting of sodium alginate, pullulan or Hypromellose or mixtures thereof.

4. The lyophilized rapidly disintegrating solid dosage form composition as claimed in claim 1, wherein, the oleaginous vehicle is selected from the group consisting of olive oil, sesame oil, castor oil, coconut oil or corn oil or mixtures thereof.

5. The lyophilized rapidly disintegrating solid dosage form composition as claimed in claim 1, wherein, the structure forming agent is Maltodextrin or Mannitol or mixtures thereof.

6. The lyophilized rapidly disintegrating solid oral dosage form composition as claimed in claims 1 to 5 comprising a pharmaceutically active substance with matrix forming agent(s) or binding agent(s) selected from the group consisting of sodium alginate, pullulan or Hypromellose or mixtures thereof; structure forming agent(s) selected from maltodextrin or mannitol or mixtures thereof together with other pharmaceutically acceptable excipients, wherein the suspension or solution or emulsion of said composition filled into the pre-formed blister pockets are freeze dried at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2followed by lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain the desired lyophilized rapidly disintegrating dosage form.

7. The lyophilized rapidly disintegrating solid oral dosage form composition as claimed in claims 1 to 5 comprising a pharmaceutically active substance as an oil in an aqueous suspension with emulsifying agent(s), matrix forming agent(s) or binding agent(s) selected from the group consisting of sodium alginate, pullulan or Hypromellose or mixtures thereof; structure forming agent(s) selected from maltodextrin or mannitol or mixtures thereof together with other pharmaceutically acceptable excipients, wherein the suspension or solution or emulsion of said composition filled into the pre-formed blister pockets are freeze dried at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2followed by lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain the desired lyophilized rapidly disintegrating dosage form.

8. The process for preparing a lyophilized rapidly disintegrating solid oral dosage form containing pharmaceutical active substance as claimed in claims 1 to 7, comprising;
i. preparing a suspension or solution or emulsion containing pharmaceutically active ingredient, binder(s), matrix forming agent(s), structure forming agent(s), optionally an oleaginous vehicle/carrier, together with other pharmaceutically acceptable excipients to obtain a homogenous suspension,
ii. transferring the homogenous suspension to a dosing tank and stirring the said suspension until the end of the filling process to obtain suspension filled blister sheets,
iii. freezing the said blister sheets at a temperature ranging from -70°C to -160°C and pressure ranging from 5 kg/cm2 to 7 kg/cm2, and
iv. lyophilizing the said blister sheets at a primary drying temperature ranging from -5°C to -35°C followed by lyophilizing at a secondary drying temperature ranging from -20°C to -40°C to obtain a rapidly disintegrating solid oral dosage.

9. The process as claimed in claim 8, wherein the solvent used in forming the solution or suspension of pharmaceutically active substance is preferably water but may be admixed with co-solvent such as alcohol.

10. The process as claimed in claim 8, wherein the blister sheets are the discrete unit blisters filled with the suspension or solution or emulsion.

11. The process as claimed in claim 10, wherein the discrete units are in the form of liquid units or solid units or gelled units.

12. The lyophilized rapidly disintegrating solid oral dosage form claimed in any of the claims 1 to 11 for delivery of the pharmaceutically active ingredient in NMT than 30 seconds.