EP1667681A1

EP1667681A1 - A novel transmucosal delivery system

Info

Publication number: EP1667681A1
Application number: EP04745093A
Authority: EP
Inventors: Jayanta Kumar Mandal; Shashank Bababhai 201 Shubh Block PATEL; Kirti Bansidhar 2 Shrinath Tween Bung MAHESHWARI; Padma Venkitachalam Devarajan
Original assignee: Astron Research Ltd
Current assignee: Astron Research Ltd
Priority date: 2003-10-03
Filing date: 2004-01-20
Publication date: 2006-06-14
Also published as: EP1667681A4; WO2005032554A1

Abstract

The novel trans mucosal dosage form of this invention relates. to -benzimidazole class of proton pump inhibitors and their precursors, derivatives or salts for the delivery of the drugs in the oral cavity. The novel transmucosal dosage forms do not require enteric coating, or any other coating or excess sodium ions commonly employed for this class of drugs. Commonly used site of absoq.)tion for this invention relates to sublingual, gingival or other oral mucosa.

Description

A NOVEL TRANSMUCOSAL DELIVERY SYSTEM

Technical Field

• The present invention relates to use of uncoated benzimidazole derivative in the form of an oral mucoadhesive tablet dosage form for sublingual, buccal, gingival administration to suppress gastric acid secretion by inhibition of the proton pump at the secretory surface of gastric parietal cells. Background of the inventions

Benzimidazole class of PPI, that inhibit gastric acid secretion are typically available as enteric coated tablets, pellets or granules or orally disintegrating tablet consisting of enteric coated drug.

The use of enteric coating of the drug is essential as this class of drugs are prone

to acid degradation. Manufacturing process for enteric coated pellets and tablets is

lengthy and cumbersome. Also, the absorption and thereby onset of action of the drug is

delayed. There is also food effect in the absorption of the drug. The drugs also undergo

extensive hepatic first pass metabolism.

For acute and chronic cases of gastric ulcer, duodenal ulcers, GERD, severe

erosive oesophagitis and other pathological hypersecretory conditions such as Zollinger

Ellison syndrome, a fast acting dosage form is the purpose of the invention. ^"•' US patents 6,498,171, 6,328,993,6365184 and 6,296,876 covers enteric coating

of PPI class of drugs.

US patent 6,328,993 claims use of a base, fatty alcohol or mixtures of fatty

alcohols and base to cover active drug units. US patent no. 6489346 covers substituted alcohols and base to cover active drug units. US patent no. 6489346 covers substituted benzimidazole dosage forms and methods of using uncoated tablets with the use of excess of buffering agents in the range of 01. m.eqύiv. to 2.5 m.equiv. per mg. of. PPI. US patent 63031147 covers bioadhesive solid dosage forms consisting of TLT 80 % pregelatinised starch.

US Patent 5,723,114 describes a method for enhancing penetration of a therapeutic or prophylactic agent and penetration enhancing compositions including transdermal and transmucosal dosage forms.

US Patent applications 20030166553 mentions among other potential pharmaceutical agents and dosage forms, proton pump inhibitors and transmucosal delivery systems.

The present invention have intensively studied the formulation aspect of uncoated

mucosal delivery tablets for achieving appropriate dissolution and stabilizing the dosage

forms. Appropriate formulation studies also have been done by the inventors to achieve.

palatability and patient's acceptance for these delivery systems. . ^•

According to the present invention, a method of producing mucosal delivery

drugs is outlined below wherein the drug Lansoprazole is either mixed in directly

compressible ingredients or granules of. the same are manufactured using wet

granulation methods. Lactose, MCC, mannitol, sucrose or glucose were used as directly compressible

vehicle and sodium bicarbonate, di sodium hydrogen orthophosphate, magnesium

carbonate, lysine, glycine and sodium hydroxide as stabilizer. Sodium Lauryl sulphate, croscarmellose sodium, crospovidone, SSG, indion (resin) were used to achieve appropriate disintegration. Sodium stearyl fumarate is used as lubricant. . Detailed Description of the invention:

The present invention relates to use of PPI' s in the uncoated form which is to be administered in oral cavity e.g. sublingual, gingival.

The invention also describes the dosage form which overcomes the destabilizing effect of PPI's by gastric juice and avoids extensive hepatic metabolism commonly encounters with this class of drugs after oral administration.

The transmucosal DDS of the present invention will also help in reducing the

onset of action and reduce dosage requirement.

For this invention, the term PPI (Proton Pump Inhibitors), shall mean any

benzimidazole class of PPI used as proton pump inhibitors. The inventive composition

comprises sublingual or other oral mucosal delivery system produced by either dry

granulation, wet granulation or direct compression method, After absorption through oral mucosal layer, drug is available to various tissues

through blood stream including parietal cells to elicit the desired pharmacological

actions.

A pharmaceutical formulation can be administered by keeping the dosage form

under the tongue (sublingual) or under the lips (gingival), or between the cheek and

gum (buccal) to aid absorption through oral mucosa without swallowing! _. Examples :. T IN2004/000013

Preparation of Tablets by Direct Compression Method

Preparation of Tablets by Dry Granulation Method

Preparation of Tablets by Wet Granulation Method

Manufacturing Process .Lansoprazole was mixed with Di Sodium Hydrogen Orthophosphate or Sodium Bicarbonate, Mannitol, Glucose Monohydrate and MCC PH 102. The blend was granulated with PVP K30 solution in Purified Water and Special Denatured Spirit in ratio of 1:1 The wet granules were dried in Tray dryer. The dried granules were mixed with lubricants and compressed into the tablets.

Preparation of Omeprazole Magnesium Tablets by Wet Granulation Methoc

Preparation of Omeprazole Magnesium Tablets by Direct Compression Method.

Preparation oi meprazoie iviagnesium ιaυιcι> υy wci «• ««■_*.« nw« ITJL I

Preparation of Omeprazole Magnesium Tablets by Direct Compression Method.

Preparation of Pantoprazole Sodium Tablets by Wet Granulation Method.

Preparation of Pantoprazole Sodium Tablets by Direct Compression Method.

Sr. Ingredients Example 4 Example 5 Example 6 No. % w/w . . % w/w :^■: % W/W Pantoprazole Sodium 14.1 14.1 14.1 Sesquihydrate Mannitol (Free Flow) 62 62 62 Di Sodium Hydrogen Orthophosphate Hydroxypropylcellulose 1.33 1.33 1.33 Sodium Stearyl Fumarate 1.33 1.33 1.33 Sodium Starch Glycolate 13.34

7 Croscarmellose Sodium 13.34 Crospovidone T3.3 Talc

10 Aspartame 1.23 1.23 1.23

11 Flavor 0.67 0.67 0.67 Hardness 2 to 5 kp 2 to 5 kp. 2 to 5 kp Disintegration Time 3 min 45 2 min 45. 2 min 30 sec sec . sec

Manufacturing Process: Pantoprazole . Sodium Sesquihydrate was mixe with Di Sodium Hydrogen Orthophosphate, Mannitol and Hydroxypropylcellulose. The blend was further blended with Sodium Stearyl Fumarate, Talc, Aspartame, Sodium Starch Glycolate or Croscarmellose Sodium or Crospovidone and Flavor. . The lubricated granules were compressed, into tablets. Preparation of Pantoprazole Sodium Tablets by Wet Granulation Method.

Preparation of Pantoprazole Sodium Tablets by Wet Granulation Method.

Preparation of Rabeprazole Sodium Tablets by Direct Compression Method.

1 Preparation of Rabeprazole Sodium Tablets by Wet Granulation Methoc

Preparation of Rabeprazole Sodium Tablets by Wet Granulation Method.

Preparation of Rabeprazole Sodium Tablets by Direct Compression Method.

While the present invention is described^' above in connection with, preferred or illustrative embodiments, these embodiments are not intended to- be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its. spirit and scope, as defined by appended claims.

Claims

We claim

1. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) characterized in that the said transmucosal delivery system comprises, (i) 2 to 50 % active pharmaceutical ingredient in dosage forms of uncoated tablets, monolithic or multilayered wherein the active pharmaceutical ingredient is incorporated in one or more layers of the tablet (ii) at least one mucoadhesive polymer in one or more layers such as cellulose ethers or alginates (iii) 50-98 % excipients such as crystalline and granular diluents which aid flow such as disodium hydrogen phosphate, sodium bicarbonate, magnesium carbonate, mannitol, (iv) stabilizers such as glycine, lysine and their organic and inorganic salts.

2. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in . claim 1 wherein the said dosage form is prepared by direct compression or granulation of the active pharmaceutical ingredient with the said excipients.

3. A novel transmucosal delivery system for oral mucosal . administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 wherein the benzimidazole proton pump inhibitor incorporated comprises of 2 to 35 % w/w of the dosage form.

4. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 wherein the benzimidazole proton pump inhibitor comprises of 5 to 30 % w/w of the dosage . form.

5. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 wherein the benzimidazole proton pump inhibitor is selected from lansoprazole, pantoprazole, rabeprazole, omeprazole and their therapeutically active precursor, derivative, salts, metabolites or similar active pharmaceutical ingredients

6. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in. claim 1 wherein the mucoadhesive polymers comprises of 1 to 30 % of the dosage form;

7. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 wherein the mucoadhesive polymers comprises of 5 to 15% of the dosage form.

8. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as clairαed in claim 1 wherein excipients containing minimum amount of or no sodium ions.

9. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1. wherein excipients are producing no effervescence.

10. A novel transmucosal delivery system for oral mucosal administration of. benzimidazole proton pump Inhibitors (PPIs) as claimed- in claim 1 wherein the said delivery system is developed to reduce on set^' time for the required pharmacological response than that due to conventional tablets, capsules, granules and multiple unit dosage (MUD) forms, dry syrups, orally disintegrating tablets and mouth dissolving tablets.

11. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 wherein the said delivery system is developed to reduce the total quantity of active drug to be administered to ge similar therapeutic effect with reduced intensity and frequency of side effects.

12. A novel transmucosal delivery system for oral mucosal administration of .-^' benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 which, is prepared to make it capable of eliminating or bypassing the extensive hepatic metabolism i.e., first-pass effect, common to the therapeutic class of drugs mentioned in claim 1.

13. A novel transmucosal delivery system for oral mucosal administration of benzimidazole proton pump Inhibitors (PPIs) as claimed in claim 1 substantially as herein described with reference to the foregoing examples.