WO2005000269A1

WO2005000269A1 - Pharmaceutical formulations comprising a proton pump inhibitor

Info

Publication number: WO2005000269A1
Application number: PCT/GB2004/002767
Authority: WO
Inventors: Amar Lulla; Geena Malhotra
Original assignee: Cipla Limited; Wain, Christopher, Paul
Priority date: 2003-06-26
Filing date: 2004-06-28
Publication date: 2005-01-06

Abstract

A pharmaceutical paste formulation for oral administration, which comprises a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, and an oily vehicle.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING A PROTON PUMP INHIBITOR

The present invention relates to improved pharmaceutical paste formulations containing proton pump inhibitors, and in particular improved pharmaceutical paste formulations containing omeprazole, and therapeutic uses thereof. Omeprazole is described in U.S. patent 4,255,432. It is a potent inhibitor of gastric acid secretion that acts by inhibiting H ^" K⁺ATPase, the enzyme involved in the final step of hydrogen ion production in the parietal cells, and has been used in the short term treatment of active duodenal and benign gastric ulcer and other gastric acid related diseases, in humans. Peptic ulcers are common also in some animals, particularly in horses. Although the etiology of gastro-duodenal ulcers in horses has not been ascertained, it appears that stress plays important roles in some cases. Omeprazole is highly acid labile and very slightly soluble in water and oral formulations have, therefore, been enteric-coated. Enteric coated formulations are expensive and time consuming to manufacture, and require elaborate technology and equipment. Another disadvantage of enteric-coated formulations is the moisture sensitivity that can often be associated with such formulations. Various formulations have been reported for proton pump inhibitors, especially for omeprazole. For example, WO94/25070 discloses an oral composition containing a proton pump inhibitor in the form of enteric-coated dry particles mixed with a dry gelling agent, the mixture may then be made into a paste-like gel prior to administration. The composition, therefore, requires enteric coating, with the aforementioned disadvantages associated with such formulation. Furthermore, because such a moist gel is not stable during long-term storage at room temperature it cannot be manufactured and sold as a ready-to-use formulation, rather it must be prepared ex tempore at the time of administration, making it inconvenient to use. U.S. patents 5,708,017 and 6,316,481 describe paste formulations of proton-pump inhibitors comprising a proton-pump inhibitor, a thickening agent, a basifying agent and hydrophobic oily liquid vehicles. The thickening agent, along with a basifying agent, provides a non-acidic environment for the acid-labile omeprazole and thus has a stabilizing effect in the formulation. The hydrophobic oily liquid vehicle comprises (i) a vegetable oil and (ii) triglycerides of medium chain fatty acids or propylene glycol diesters of medium chain fatty acids. The lubricant properties of the oil help the paste formulation to attain a desired degree of cohesiveness, plasticity, tenacity and ejectability. Also, GB patent application 0225926A describes paste formulation of proton pump inhibitors along with surfactant, plasticizer and an amphiphillic base. However, the common problem of syneresis, or separation of liquid from paste with time, has been reported with formulations as described in U.S. patents 5,708,017 and 6,316,481. Hence, there remains a need for pharmaceutical paste formulations having a blend of excipients that would alleviate the problems associated with prior art formulations for thermolabile and moisture sensitive drugs. The present invention now provides a stable, improved paste formulation for proton pump inhibitors. More particularly, there is provided by the present invention a pharmaceutical paste formulation for oral administration, which comprises a proton pump inhibitor and an oily vehicle, which yields stable formulation on storage. The proton pump inhibitors, or pharmaceutically acceptable salts, derivatives or enantiomers thereof, used in the present invention are known compounds in the art, and methods for their preparation may be found in the literature. For example omeprazole is disclosed in EP patent 5129B, lansoprazole in EP patent 174726B, pantoprazole in EP patent 166287B and lemiprazole in GB patent 2,163,747B. The preferred proton pump inhibitor used in the present invention is the compound known as omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof. The term "proton pump inhibitors" is used herein in a broad sense to include not only proton pump inhibitors per se, but also pharmaceutically acceptable salts, derivatives and enantiomers thereof. Omeprazole is known to have poor intrinsic aqueous solubility and / or poor wetting capability, which has reduced the efficiency of its solubilization within the gastrointestinal milieu when present in prior art pharmaceutical formulations. This reduction in solubility has led to poor bioavailability of omeprazole in prior art formulations. We have now found that the use of an oily vehicle in formulations according to the present invention can achieve improved bioavailability of a proton pump inhibitor present in a formulation according to the present invention. In particular, we have found that it is preferred to incorporate an oily vehicle, such as liquid paraffin, to increase the bioavailability of the proton pump inhibitor present in a formulation according to the present invention. Examples of suitable oily vehicles for use in a formulation according to the present invention include liquid paraffins, petroleum jelly, normal paraffins, waxes, petrolatum, and derivatives thereof. The oily vehicle employed in a formulation according to the present invention may additionally provide solubilizing, emollient, solvent and / or plasticizing properties and the like to the formulation and thus can increase the solubility of a proton pump inhibitor, such as omeprazole, present in the formulation. In this way, a stable paste formulation can be provided by the present invention for acid labile and poorly soluble proton pump inhibitors, such as omeprazole. A particularly preferred pharmaceutical paste formulation for oral administration according to the present invention comprises a proton pump inhibitor which is omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, and an oily vehicle which is preferably liquid paraffin. There is further provided by the present invention use of liquid paraffin as an oily vehicle for a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, in a pharmaceutical paste formulation, whereby said proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, is provided in stabilised form in said formulation. There is also provided by the present invention, use of liquid paraffin to increase the bioavailability of a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, when present in a pharmaceutical formulation. Suitably this use in increasing bioavailability can be further characterised by the use of the liquid paraffin as an oily vehicle for the proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof. Substantially as hereinbefore described, it is preferred that the proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof is omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof. A formulation according to the present invention may optionally include suitable thickening agents selected from the group consisting of aluminum stearates, such as aluminium monostearate, aluminium distearate and the like. The amount of thickening agent employed in the formulation can vary, and suitably can be in the range of about 0 to 3%w/w, based on the weight of the total formulation and preferably in the range of about 0.3 to 1.5%w/w based on the weight of the total formulation. A formulation according to the present invention may also include additional ingredients commonly used in the formulation of human and veterinary medicines. For example, flavoring agents such as caramel, carrot, apple, cinnamon and sausage flavors; and coloring agents such as iron oxides, titanium dioxide, aluminum lakes and the like, can be added. The amount of a proton pump inhibitor employed in a formulation according to the present invention can vary, and suitably can be in the range of about 1 to 50%w/w, based on the weight of the total formulation. Preferably the amount is about 50%w/w or less, based on the weight of the total formulation, and more preferably in the range of about 30 to about 40%w/w, based on the weight of the total formulation. An oily vehicle is suitably included in a formulation according to the present invention in the range of about 50 to 70%w/w, based on the weight of the total formulation. The incorporation of an acid labile drag substance, namely a proton pump inhibitor, in a formulation according to the present invention, results in an orally palatable and pharmaceutically stable paste. A paste formulation according to the present invention, and a pharmacologically active proton pump inhibitor contained therein, exhibit good stability. Formulations according to the present invention are useful in the treatment of peptic ulcer diseases in humans or animals and can be used to deliver acid labile proton pump inhibitors orally for systemic activity in animals. The formulations of the present invention may be administered directly into the mouth of an animal, such as a horse, in need of anti- ulcer therapy; and preferably a paste-dosing syringe can be used to facilitate drug administration. The consistency of a paste formulation according to the present invention is preferably such that it cannot easily drip out or be expelled once it is deposited on the dorsal part of an animal's tongue. The paste is essentially free of air bubbles, which enhances dosing accuracy. There is also provided by the present invention a method of treating a human or animal patient suffering from or susceptible to a peptic ulcer or related disease, which method comprises administering to the human or animal patient a therapeutically effective amount of a formulation according to the present invention. The term "treatment" as used herein refers to prophylaxis in susceptible patients, as well as the treatment of established symptoms of peptic ulcer or related disease. The present invention also provides a process of preparing a stable, improved paste formulation for a proton pump inhibitor, such as omeprazole, substantially as hereinbefore described, which process comprises admixing the proton pump inhibitor, and an oily vehicle substantially as hereinbefore described, so as to yield a formulation according to the present invention, which formulation can suitably be colored and / or flavored. More particularly, a formulation according to the present invention can be prepared by dispersing the proton pump inhibitor, in powder form, in an oily vehicle optionally containing coloring agents, at a controlled temperature. A flavoring agent may then be added and mixed and homogenized to achieve desired consistency. A paste formulation thus obtained may be used to fill dosing syringes, which may be used directly to administer proton pump inhibitors to an animal in need of such treatment. The present invention will now be further illustrated by the following Examples, which do not limit the scope of the invention in any way.

Example 1

Color was added to light liquid paraffin, under stirring. To the color dispersion was then added omeprazole with mixing. Finally flavor was added, and mixing continued until a homogeneous mass was obtained.

Example 2

Example 3

Aluminium monostearate was dissolved in liquid paraffin. To this color was added under stirring. To the color dispersion was then added omeprazole with mixing. Finally flavor was added, and mixing continued until a homogeneous mass was obtained.

Claims

1. A pharmaceutical paste formulation for oral administration, which comprises a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, and an oily vehicle.

2. A pharmaceutical formulation according to claim 1, wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, pantoprazole and lemiprazole, or pharmaceutically acceptable salts, derivatives or enantiomers thereof.

3. A pharmaceutical formulation according to claim 2, wherein the proton pump inhibitor is omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof.

4. A pharmaceutical formulation according to any of claims 1 to 3, wherein the oily vehicle is selected from the group consisting of liquid paraffins, petroleum jelly, paraffins, waxes, petrolatum and derivatives thereof.

5. A pharmaceutical formulation according to claim 4, wherein the oily vehicle is liquid paraffin.

6. A pharmaceutical paste formulation for oral administration, which comprises a proton pump inhibitor which is omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, and an oily vehicle which is liquid paraffin.

7. A pharmaceutical formulation according to any of claims 1 to 6, wherein the oily vehicle is present in an amount in the range of about 50 to 70%w/w, based on the weight of the total formulation.

8. A pharmaceutical formulation according to any of claims 1 to 7, wherein the proton pump inhibitor is present in an amount in the range of about 1 to 50%w/w, based on the weight of the total formulation.

9. A pharmaceutical formulation according to claim 8, wherein the proton pump inhibitor is present in an amount in the range of about 30 to about 40%w/w, based on the weight of the total formulation.

10. A pharmaceutical formulation according to any of claims 1 to 7, which further comprises a thickener selected from the group consisting of aluminum stearates.

11. A pharmaceutical formulation according to claim 10, wherein said thickener is aluminium monostearate.

12. A method of treating a human or animal patient suffering from or susceptible to a peptic ulcer or related disease, which method comprises administering to the human or animal patient a therapeutically effective amount of a formulation according to any of claims l to ll.

13. A process of preparing a pharmaceutical formulation according to any of claims 1 to 11, which process comprises admixing a proton pump inhibitor and an oily vehicle, so as to yield a formulation according to any of claims 1 to 11.

14. A process according to claim 13, which comprises dispersing the proton pump inhibitor, in powder form, in an oily vehicle optionally containing colouring agents, at a controlled temperature.

15. Use of liquid paraffin as an oily vehicle for a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, in a pharmaceutical paste formulation, whereby said proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, is provided in stabilised form in said formulation.

16. Use of liquid paraffin to increase the bioavailability of a proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, when present in a pharmaceutical formulation.

17. Use according to claim 16, wherein said liquid paraffin is present as an oily vehicle for the proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof.

18. Use according to any of claims 15 to 17, wherein said proton pump inhibitor, or a pharmaceutically acceptable salt, derivative or enantiomer thereof, is omeprazole, or a pharmaceutically acceptable salt, derivative or enantiomer thereof.