Title of Invention

A NASAL DRUG DELIVERY SYSTEM OF ONDANSETRON HYDROCHLORIDE AND PROCESS FOR PREPARATION THEREOF

Abstract

The present invention relates to novel nasal drug delivery system of Ondansetron Hydrochloride in form of nasal spray and process for preparation thereof. The nasal mucosa is more sensitive to external influences, large and easily accessible area of highly permeable, vascularized tissue through which drugs absorbed rapidly and directly into systemic circulation. Invented Nasal spray in the form of solution, suspension, emulsion, gel and in-situ gel are absorbed rapidly and directly into systemic circulation. Nasal spray is developed by using the process of thermoforming in-situ gel technique. Nasal spray formulation comprises Ondansetron HCl 0.01-0.03%, Citric Acid 0.145%, Disodium Hydrogen Phosphate 0.256%, Disodium Edetate 0.100%, Sodium Chloride 0.37%, Benzalkonium Chloride solution 0.02%, Sodium Hydroxide Quantity sufficient, Cross Carmellose sodium CL 611 is 1.5%, Creamophor RH 40 is 1.0%, xyletol 8.0%, Hydroxy Propyl Cellulose 0.3%, Carbopol 934P 0.4%, Water Quantity sufficient of the total composition by volume.

Full Text

FORM - 2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION [SECTION 10] 1. A NASAL DRUG DELIVERY SYSTEM OF ONDANSETRON HYDROCHLORIDE AND PROCESS FOR PREPARATION THEREOF. 2. (a) LINCOLN PHARMACEUTICALS LIMITED. (b) Nirav Complex, Opp. Navrang High school, Naranpura, Ahmedabad-380014. Gujarat State, India. (c) Nationality: Indian. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed. The present invention relates to a novel nasal drug delivery system of Ondansetron Hydrochloride and process for preparation thereof. The object of the present invention is to provide a novel nasal drug delivery system comprising Ondansetron Hydrochloride for fast onset of antiemetic action in treatment of postoperative nausea and vomiting. One another object of the present invention is to provide a novel nasal drug delivery system of Ondansetron Hydrochloride with no side effects such as vomiting and nausea associated with emetogenic chemotherapy, including high dose cisplatin, and radiotherapy. The another object of the present invention is to provide novel nasal drug delivery system comprising Ondansetron Hydrochloride propose the patients to self medicate, avoid the risk of needle-stick injuries and biohazardous waste. PRIOR ART: Ondansetron is selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area posterma, located on the floor of the fourth ventricle. Thus the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Many compounds, particularly macromolecules, are not adequately bioavailable when delivered orally or are associated with adverse gastrointestinal effects. Children and elders orally administered antiemetic dose for the treatment of nausea & vomiting has difficulty in swallowing tablets or capsules. In addition to this orally administered drug takes longer time to reach the blood stream. Prophylactic administration of intravenous ondansetron 4mg/l hour before skin closure is safe and effective in preventing Post Operative nausea & Vomiting (PONV) in female patients undergoing breast surgery and routine use of ondansetron in the patient is also recommended. [J Indian Med Assoc. 2004 Feb; 102(2): 73-4, 76, 78-9.] [PMID: 15200199] Combined treatment with ondansetron injection and tablet was considered clinically useful in control of nausea and vomiting during administration of carboplatin, and may also be useful for outpatient chemotherapy. [Gan To Kagaku Ryoho. 1999 Jan; 26(1): 125-30.] [PMID: 9987508] Specific concentrations of cisplatin, 5-fluorouracil, carboplatin, etoposide, ceftazidime, cyclophosphamide and doxorubicin are compatible when administered via a giving set delivering ondansetron by infusion. [Eur J Cancer Clin Oncol. 1989; 25 Suppl l:S67-9.] [PMID: 2533902] Ondansetron has no adverse cardiovascular effects within 10 minutes of administration, i.m. prochlorperazine and i.v. Ondansetron reduce PONV more effectively than i.v. Prochlorperazine and postoperative headache after septorhinoplasty occurs less frequently in those given i.m. Prochlorperazine than in those given i.v. Ondansetron. [Anaesth Intensive Care. 1996 Oct; 24(5): 538-45.] [PMID: 8909662] Ondansetron does not appear to be associated with an increased risk for major malformations above baseline. [BJOG. 2004 Sep; 111(9): 940-3.] [PMID: 15327608] Ondansetron is available in various dosage forms -tablets, injection, and solution for oral as well as parentral administration. U.S. Patent 2004019093 based on novel crystal forms of ondansetron, process for their preparation, pharmaceutical compositions containing the novel forms and method for their preparation. U.S. 2004136914 based on buccal, polar and non-polar spray containing ondansetron. U.S. 6,610,271 based on intranasal phrmaceutical drug compositions and preparation of Lorazepam. In which Lorazepam preparations for treatment of anxiety related disorders, fntranasal compositions consisting of Lorazepam, Polyethylene glycol, propylene glycol, sweetener. The said intranasal do not give the antiemetic action. Oral dosage forms and parental forms may not be convenient, patient-friendly, need help to patients for intake of water, for swallow the tablet. Also these dosage forms do not get absorbed rapidly and directly in systemic circulation. To comeover from drawback of such dosage forms a new dosage form of Ondansetron Hydrochloride is invented. A novel nasal drug delivery system is developed; causes sustained systematic drug absorption and eliminate the chances of draining off from nasal passages. It is therefore, a principle object of the present invention to provide a novel formulation of ondansetron in form of nasal spray for prompt and alternative formulation spray form and a unique process of the preparation thereof. Nasal passages and other portions of the respiratory tract are lined with specialized tissue layers, called the nasal mucosa. Nasal mucosa is much more sensitive to external influences than the digestive mucosa in the stomach also a large and easily accessible area of highly permeable and vascularized tissue through which drugs can be absorbed rapidly and directly into systemic circulation, which could be especially important in the management of crisis situations and intense acute pain, such as a heart attack, hypoglycemia, seizure, severe nausea and vomiting, or breakthrough cancer pain. Drug delivery through nasal mucosa avoids drug degradation in the gastrointestinal tract. Low dosage form is also adequate to cure nausea and vomiting on administer through the nasal route. Nasal route administration of certain medicaments also offers reduced side effects. DETAILED DESCRIPTION OF INVENTION: The novelty of the invention and other advantages of the present invention, in addition to those mentioned above will become apparent to those skilled in the art from the following detailed description. A novel nasal drug delivery system comprising the antiemetic drug Ondansetron Hydrochloride. In the present invention, formulation of novel drug delivery system is developed in form of nasal spray. Novel nasal spray is formulated in thermoforming in-situ gel form. The present invention also based on process for preparation of novel nasal drug delivery system. Using the process of thermoforming in-situ gel technique, which ensures sustained systematic drug absorption and eliminate the chances of draining off from nasal passages develops the novel drug delivery system. Presently invented nasal spray contains active pharmaceutical drug ondansetron, chelating agent Disodium Edetate, pH adjustant Sodium Chloride, buffering agents Citric Acid & Disodium Hydrogen Phosphate, preservative as antimicrobial agent Benzalkonium Chloride Solution, gelling agent Hydroxy Propyl Cellulose, emulsifying agent Cremophor RH 40, suspending agents Cross Carmellose sodium CL 611 & Sodium Hydroxide, Water as solvent, wetting agent, thermoforming gelling agents Pluronic F 127, Carbopol 940. Nasal spray formulation of the present invention comprises: Ondansetron HC1 - 0.02% wt/ volume of formulation Citric Acid - 0.145% wt/ volume of formulation Disodium Hydrogen Phosphate- 0.256% wt/ volume of formulation Disodium Edetate - 0.100% wt/ volume of formulation Sodium Chloride - 0.37% wt/ volume of formulation Benzalkonium Chloride solution - 0.02% wt/ volume of formulation Sodium Hydroxide - Quantity sufficient Cross Carmellose sodium CL 611 -1.5% wt/ volume of formulation Creamophor RH 40 - 1.0% wt/volume of formulation Xyletol - 8.0% wt/volume of formulation Hydroxy Propyl Cellulose - 0.3% wt/volume of formulation SCarbopol 934 P - 0.4% wt/volume of formulation Water - Quantity sufficient. Ondansetron Hydrochloride used in the preparation of thermoforming in-situ gel form of the novel nasal spray is 0.01% to 0.03% wt/volume of formulation. A process is developed to prepare a novel nasal spray formulation comprising Ondansetron Hydrochloride. Process for preparation of nasal spray in thermoforming in-situ gel form: Nasal spray in thermoforming in-situ gel form is prepared by: Taking 67% to 68% water of the total composition by volume; adding 0.02% Ondansetron Hydrochloride and citrophosphate buffer about 0.401% of the total composition by volume. Further adding chelating agent 0.100% and pH adjustant 0.37% of the total composition by volume; adding thermoforming gelling agent 15.4% and preservative about 0.02% of the total composition by volume and adjusting the pH 4 to 8 by adding base. The said thermoforming gel form is filled in the containers and containers are fitted with the metered pump valve and actuator. Finally containers are labeled and cartoned. Novel nasal drug delivery system comprising Ondansetron Hydrochloride prepared by using above mentioned method gives faster onset of therapeutic action within few minutes. Novel nasal spray dosage form prepared using Ondansetron Hydrochloride and other excipients gives synergistic effect in treatment of antiemetic condition. Spraying the dosage form through nasal mucosa rapidly exerts its antiemetic effect. EXAMPLES: The present invention is described in more detail by examples, but the examples are only illustrative and, therefore, not intended to limit the scope of the present invention. Example: Nasal spray in thermoforming in-situ gel form: Ondansetron HC1 0.02% Citric Acid 0.145% Disodium Hydrogen Phosphate 0.256% Disodium Edetate 0.100% Benzalkonium Chloride Solution 0.02% Pluronic F 127 15% Carbopol 940 0.4% We claim, 1. A nasal drug delivery system in spray or thermoforming in-situ gel form of Ondansetron Hydrochloride, wherein the drug delivery system comprising of active pharmaceutical ingredient Ondansetron HC1 in the range from between 0.01% to 0.03%, Citric Acid 0.145%, Disodium Hydrogen Phosphate 0.256%, Disodium Edetate 0.100%, Sodium Chloride 0.37%, Benzalkonium Chloride solution 0.02%, Sodium Hydroxide Quantity sufficient, Cross Carmellose sodium CL 611 is 1.5%, Creamophor RH 40 is 1.0%, xyletol 8.0%, Hydroxy Propyl Cellulose 0.3%, Carbopol 934 P 0.4%, Water Quantity sufficient of the total composition by volume. 2. A nasal drug delivery system of Ondansetron Hydrochloride as claimed in claim 1 wherein Ondansetron Hydrochloride is preferably in amount 0.02% of the total composition by volume. 3. A process for the preparation of a nasal drug delivery system (NDDS) of Ondansetron Hydrochloride as claimed in claim 1 & 2 wherein nasal spray is formulated in solution form: taking 67% to 68%o water of the total composition by volume; adding Ondansetron hydrochloride 0.02% and citrophosphate buffer 0.401% of the total composition by volume, further adding 0.100% chelating agent Disodium Edetate and 0.37% pH adjustant Sodium Chloride of the total composition by volume; adding 0.02% preservative Benzalkonium Chloride Solution of the total composition by volume and adjust the pH 4 to 8 by adding base; finally prepared solution is filtered by using sterile 0.2 filter; the filtered solution is filled in the containers and containers are fitted with the metered pump valve and actuator. 4. A nasal drug delivery system of Ondansetron Hydrochloride substantially herein described with foregoing description and examples. Dated this on 25th of December, 2004. Dr. Rajeshkumar H. Acharya. Advocate & Patent agent For and on behalf of the applicant.

Documents:

1421-mum-2004-abstract(28-12-2004).doc

1421-mum-2004-abstract(28-12-2004).pdf

1421-mum-2004-cancelled pages-(8-11-2006).pdf

1421-mum-2004-claims(granted)-(28-12-2004).doc

1421-mum-2004-claims(granted)-(8-11-2006).pdf

1421-mum-2004-correspondence(8-11-2006).pdf

1421-mum-2004-correspondence(ipo)-(20-8-2007).pdf

1421-mum-2004-declaration(28-12-2004).pdf

1421-mum-2004-form 1(28-12-2004).pdf

1421-mum-2004-form 18(5-8-2005).pdf

1421-mum-2004-form 2(granted)-(28-12-2004).doc

1421-mum-2004-form 2(granted)-(8-11-2006).pdf

1421-mum-2004-form 26(28-12-2004).pdf

1421-mum-2004-form 3(28-12-2004).pdf

1421-mum-2004-form 5(28-12-2004).pdf

1421-mum-2004-form 9(2-8-2005).pdf