WO2009145905A1

WO2009145905A1 - Dosage forms for the rapid and sustained elevation of gastric ph

Info

Publication number: WO2009145905A1
Application number: PCT/US2009/003281
Authority: WO
Inventors: John R. Plachetka
Original assignee: Pozen Inc.
Priority date: 2008-05-30
Filing date: 2009-05-29
Publication date: 2009-12-03
Also published as: EP2364145A1; CA2740974A1; EP2364145A4

Abstract

The present invention is directed to pharmaceutical compositions and dosage forms that can be used to treat diseases characterized by abnormal gastric acid secretion. The dosage forms are designed to immediately release both a proton pump inhibitor (ppi) and an H2 blocker.

Description

Dosage Forms for the Rapid and Sustained Elevation of Gastric pH

Cross Reference to Related Applications

The present application claims priority to, and the benefit of, United States provisional application 61/129,029 filed on May 30, 2008, the contents of which is hereby incorporated by reference in its entirety.

Field of the Invention

The present invention is directed to orally administered pharmaceutical compositions that rapidly elevate the gastric pH of a patient. The pharmaceutical compositions include at least one H2 blocker and at least one proton pump inhibitor, both of which are released immediately after ingestion. The compositions may be used in the treatment of gastrointestinal disorders, and particularly for the treatment of gastroesophageal reflux disease.

Background of the Invention

The ability to regulate gastric pH is important in the treatment of gastroesophogeal reflux disease (GERD), in maintaining the integrity of acid labile drugs and in preventing the development of gastrointestinal lesions associated with the administration of certain drugs, particularly NSAIDs (see U.S. 6,926,907 and WO 2004/060372). Two types of agents frequently prescribed for regulating gastric pH are H2 blockers and proton pump inhibitors. H2 blockers have a relatively rapid onset of action but a short duration of effectiveness (typically 8-12 hours). As a result, these agents provide rapid relief but may not provide sufficient protection for patients with more severe forms of GERD or for patients chronically taking NSAIDs. Examples of H2 blockers currently on the market are: cimetidine (Tagamet®); famotidine (Pepcid®); nizatidine (Axid®); and ranitidine (Zantac®)

Proton pump inhibitors (PPIs) inhibit the enzyme responsible for secreting acid into the stomach and typically have a duration of action long enough that they only need to be taken once a day. However, most proton pump inhibitors are acid labile. As a result, they are usually enterically coated and this contributes to a very slow onset of effectiveness (see

U.S. 4,853,230; 4,786,505; EP 0277,741; and EP 0342,522). Patients taking PPIs usually do not get substantial relief from their symptoms for at least 24 hours after ingestion and several days may be required {Clin. Pharmakinet 20:38-49(1991)). Recently, attempts have been made to reduce the time needed for achieving a therapeutic effect by using dosage forms that release PPIs immediately after ingestion along with an antacid buffer to raise gastric pH (U.S. 5,840,737; 6,489,346; 6,645,988; 6,780,882; 4,786,505; and 6,183,776). Examples of proton pump inhibitors are: omeprazole (Prilosec®); esomeprazole (Nexium®); lansoprazole (Prevacid®); pantoprazole (Protonix®); rabeprazole (Aciphex®), tenatoprazole and s-tenatoprazole. "Reversible proton pump inhibitors" and "acid pump antagonists" that are less susceptible to acid degradation include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO9605177 and WO9605199).

Although the PPIs are most commonly used in the treatment of severe GERD, they have also been used to reduce the risk of gastrointestinal lesions in patients taking NSAIDs (U.S. 5,204,118; U.S. 5,417,980; U.S. 5,466,436; U.S. 5,037,815; and 6,365,184). However, the slow onset of effectiveness associated with these drugs is a serious disadvantage in a medication designed to relieve acute symptoms. In addition, attempts to reduce the risk of gastrointestinal ulcers using PPIs alone appears not to have been met with complete success. Despite a significant reduction in gastroduodenal lesions with the concomitant administration of a proton pump inhibitor during six months of NSAID therapy, up to 16% of patients still develop ulcers (N. Eng. J. Med. 338:727-734 (1998)).

Summary of the Invention

The present invention is based upon the development of dosage forms for oral administration that provide for both the rapid and long term elevation of gastric pH. This is accomplished by releasing both a PPI and an H2 blocker from the dosage forms immediately after ingestion. The dosage forms may be used to treat patients for diseases characterized by abnormal gastric acid secretion, especially gastric esophageal reflux disease.

In its first aspect, the invention is directed to a pharmaceutical composition in unit dosage form for oral administration to a patient which contains both a therapeutically effective amount of a proton pump inhibitor (ppi), and a therapeutically effective amount of an H2 blocker. The term "therapeutically effective amount" means that, upon ingestion of one or more unit dosage forms by a patient, sufficient drug is present to achieve the desired therapeutic effect. For example a "therapeutically effective amount" of a ppi means that there is a sufficient amount of drug to produce an increase in the median of gastric pH measurements taken at regular intervals over a 24 hour period. Therapeutically effective dosages for the PPIs and H2 blockers specifically recited herein are well known in the art.

The dosage forms are designed so that at least 10%, and preferably at least 20% or 50%, of both the ppi and the H2 blocker are released into the stomach of a patient within fifteen minutes, and preferably within ten, five or three minutes, after ingestion as determined using standard in vivo or in vitro methods. Unless otherwise indicated, all percentages herein are weight percentages. For example, in a tablet with 10 mg of a ppi, 10 mg of an H2 blocker and 80 mg of other components, the ppi and H2 blocker would each be present at 10%. Ten percent of both the ppi and the H2 blocker in this tablet would be released when 1 mg of ppi and 1 mg of H2 blocker were released. In other dosage forms of the invention, at least 1 mg (and preferably 5 or 10 mg) of a ppi and at least 1 mg (and preferably 5 or 10 mg) of an H2 blocker are released within fifteen minutes and preferably within ten, five or three minutes after ingestion, regardless of the percentage of total drug this represents. Again, the amount released may be determined using either standard in vivo or in vitro methods.

In order to allow for immediate release, at least a portion (and preferably all) of the ppi and the H2 blocker must be free of agents or barriers that retard dissolution, e.g., at least a portion (and optionally all) of these drugs must not be surrounded by an enteric coating. Small amounts of buffer may be present in dosage forms to stabilize the drugs but the total amount of buffer should not exceed 15 mg, and preferably should not exceed 5 mg or 1 mg. After administration, the pH in the stomach of a patient with a gastric pH of 2.5 or less should rise to 3.5 or higher within 45 minutes, and preferably within 30 or 20 minutes. pH should remain elevated at or above 3.5 for at least 2 hours, and preferably for at least 6, 8, 10, 12 or 16 hours.

The PPIs used in dosage forms should typically be present at 1-200 mg and are preferably selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole, S-tenatoprazole and rabeprazole. Particularly preferred are dosage forms having a ppi selected from the group consisting of: omeprazole, present at between 5 mg and 50 mg; esomeprazole, present at 5-100 mg; lansoprazole, present at 15- 150 mg; pantoprazole, present at between 10 mg and 200 mg; and rabeprazole, present at between 5 mg and 100 mg.

Preferably, H2 blockers are present in dosage forms at 1-300 mg and are selected from the group consisting of: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine. Especially preferred are dosage forms having: cimetidine at 100 to 800 mg; ranitidine at 50-300 mg; famotidine at 5-100 mg; ebrotidine at 400-800 mg/unit dose; pabutidine at 40 mg/unit dose; lafutidine at 5-20 mg; and nizatidine at 50-600 mg.

The dosage forms may be tablets, capsules or powders and have the ppi and the H2 blocker in admixture. Alternatively, the dosage forms may be multilayer tablets in which essentially all of the ppi is in one layer and essentially all of the H2 blocker is in a separate layer. The term "essentially all" refers to greater than 90% (and preferably greater than 95% or 99%) of the total amount of a drug present. Optionally, the layer containing the ppi and/or the layer containing said H2 blocker also includes at least one disintegrant and/or a compound that causes effervescence. Disintegrants that may be used include: croscarmellose sodium, crospovidone, sodium starch glycolate, povidone, crosslinked polyvinylpyrrolidone, starch, low substituted hydroxymethylcellulose, methylcellulose, micro crystalline cellulose.

In another aspect, the invention is directed to method of treating a patient for a disease or condition characterized by abnormal gastric acid production, especially gastric acid reflux disease. Treatment involves administering to the patient any of the dosage forms above. The invention also includes a method of treating a patient for pain or inflammation, by administering one of the NSAID-containing dosage forms described above.

Definitions A. "Unit dose" or "unit dosage form" refers to a single drug administration entity.

By way of example, a single tablet or capsule would be a unit dosage form. B. "Proton pump inhibitors" are drugs (usually benzimidazole derivatives) that block gastric acid secretion by irreversibly inhibiting H /K⁺ ATPase. Examples include omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.

C. "H2 blockers" as used herein is synonymous with "H₂-receptor antagonist" or

"H₂ antagonist." These drugs block the action of histamine on parietal cells in the stomach, thereby decreasing acid production by these cells. Examples include: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine.

D. A "disease or condition characterized by abnormal gastric acid production" includes all diseases and conditions in which acid secretion: a) is abnormally elevated; b) occurs at inappropriate times; or c) results in the irritation of the esophagus or other organs. The term includes: dyspepsia, peptic ulcers, Zollinger-Ellison syndrome, and gastroesophageal reflux disease (GORD/GERD).

E. "Therapeutically effective amount" as to drug dosage shall mean a dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. For drugs already on the market, a therapeutically effective amount shall include dosages that have been determined as safe and effective for any indication. Nevertheless, this does not necessarily exclude substantially lesser (or greater) dosages than established minimum (or maximum) dosages in particular cases.

F. "Onset of action" refers to the interval that begins when a drug is first ingested by a patient and that ends when a therapeutic effect is first observed.

G. "Co-timely" with respect to drug administration refers to the administration of a second drug for the treatment of a condition while a first drug is still present in a therapeutically effective amount.

H. "Multilayer tablet" refers to a tablet dosage form in which components are found in two or more distinct regions. For example, a multilayer tablet may contain an outer layer in which an H2 blocker is essentially the only active agent and an inner layer in which essentially the only active agent is a PPI antagonist.

I. "Pharmaceutical composition" refers to a composition containing the drug combinations described herein together with one or more pharmaceutically acceptable carriers or excipients. Typical excipients would include buffering agents (e.g., phosphate or bicarbonate buffers); binders (e.g., polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose

(HPC), hydroxypropyl methyl cellulose (HPMC)); plasticizers (e.g., polysorbates; dimethyl phthalate, diethyl phthalate, triacetin, triethyl citrate, and polyethylene glycol (PEG)); lubricants (e.g., magnesium stearate); disintegrants (e.g., croscarmellose salts) etc.

Flavoring agents, coloring agents and coatings may also be present.

Detailed Description of the Invention

The present invention is directed to dosage forms that provide for the quick release of both a ppi and an H2 blocker and which may be used to elevate the gastric pH of a patient. These drugs are well known in the art and the preferred agents described herein are commercially available. If desired, drugs can also be manufactured using methodology well known in the art.

It will be understood that the drugs used in dosage forms, i.e., PPIs, H2 blockers and

NSAIDs, may be used in any pharmaceutically acceptable form, e.g. they may be in the form of an acid, base or salt. Unless otherwise indicated the recitation of any drug herein encompasses all these different forms of the drug. However, the weights and percentages recited refer to the free form of the drug. Thus, a composition having 10 mg of naproxen would have the same amount of this drug even though different salt forms may be used.

Making of Pharmaceutical Preparations

The pharmaceutical compositions and dosage forms of the present invention can be made in accordance with methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16^th edition, A. Oslow, editor, Easton, PA (1980)). Drugs may be prepared in admixture with conventional excipients, carriers, buffers, flavoring agents, etc. Typical carriers include, but are not limited to: water; salt solutions; alcohols; gum arabic; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates, such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc. Pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants; preservatives; disintegrants; stabilizers such as cyclodextrans; wetting agents; emulsifϊers; salts; buffers; coloring agents; flavoring agents; or aromatic substances. Tablets can be made using standard technology well known in the art. Drugs may be granulated by methods such as slugging, low-shear or high-shear granulation, wet granulation, or fluidized bed granulation. Outer coatings may be formed by preparing a mixture containing appropriate polymers.

It is expected that a skilled pharmacologist will adjust the amount of drug in a pharmaceutical composition or administered to a patient based upon standard techniques well known in the art. Nevertheless, the following general guidelines are provided:

With respect to H2 blockers and PPIs, unit dosage forms may contain anywhere from 1 mg to as much as Ig. Typical amounts for H2 blockers are: cimetidine, 100 to 800 mg/unit dose; ranitidine, 50-300 mg/unit dose; famotidine, 5-100 mg/unit dose; ebrotidine 400 - 800 mg/unit dose; pabutidine 40 mg/unit dose; lafutidine 5-20 mg/unit dose; and nizatidine, 50-600 mg/unit dose. Proton pump inhibitors will typically be present at about 5 mg to 600 mg per unit dose. For example, the proton pump inhibitor omeprazole should be present in an amount from 5 to 50 mg, with about 10 or 20 mg being preferred. Other typical amounts are: esomeprazole, 5-100 mg, with about 40 mg being preferred; lansoprazole, 5-150 mg (preferably 5-50 mg), with about 7.5, 15 or 30 mg being most preferred; pantoprazole, 10-200 mg, with about 40 mg being preferred; and rabeprazole, 5- 100 mg, with about 20 mg being preferred.

Treatment of Patients

The pharmaceutical compositions described above can be used to treat a patient for any disease or condition in which proton pump inhibitors are indicated. Common conditions will include GERD, duodenal ulcers, gastric ulcers, severe erosive esophagitis, and

Zollinger Ellison syndrome In all cases, a patient should be administered a sufficient daily dosage to eliminate the symptoms associated with excess gastric acid production. Typical daily dosages of all of the preferred agents are well known in the art. As a general rule, drugs will be designed to be taken once a day but other dosing regimens may also be used.

All references cited herein are fully incorporated herein by reference. Having now fully described the invention, it will be understood by those of skill in the art that the invention may be performed within a wide and equivalent range of conditions, parameters and the like, without affecting the spirit or scope of the invention or any embodiment thereof.

Claims

What is Claimed is:

1. A pharmaceutical composition in unit dosage form for oral administration to a patient comprising: a therapeutically effective amount of a proton pump inhibitor (ppi), and a therapeutically effective amount of an H2 blocker, wherein: a) at least 10% of both said ppi and said H2 blocker are released from said dosage form into the stomach of said patient within fifteen minutes after ingestion and/or at least 1 mg of said ppi and said H2 blocker are released from said dosage form into the stomach of said patient within fifteen minutes after ingestion; b) at least a portion of both said ppi and said H2 blocker are not surrounded by an enteric coating; c) said dosage form contains no more than 15 mg of buffer.

2. The pharmaceutical composition of claim 1, wherein, after ingestion by a patient with a gastric pH of 2.5 or less, said gastric pH rises to at least 3.5 within 45 minutes and remains at or above 3.5 for at least 6 hours.

3. The pharmaceutical composition of claim 2, wherein said gastric pH rises to at least 3.5 within 30 minutes after ingestion and remains at or above 3.5 for at least 24 hours.

4. The pharmaceutical composition form of claim 1, wherein none of the ppi and none of the H2 blocker in said dosage form are surrounded by an enteric coating.

5. The pharmaceutical composition of claim 4, wherein: a) at least 20% of both said ppi and said H2 blocker are released from said dosage form into the stomach of said patient within ten minutes after ingestion; and b) after ingestion by a patient with a gastric pH of 2.5 or less, said gastric pH rises to at least 3.5 within 45 minutes and remains at or above 3.5 for at least 12 hours.

6. The pharmaceutical composition of claim 5, wherein said gastric pH rises to at least 3.5 within 30 minutes after ingestion and remains at or above 3.5 for at least 24 hours.

7. The pharmaceutical composition of claim 1, wherein: a) at least 5 mg of both said ppi and said H2 blocker are released from said dosage form into the stomach of said patient within five minutes after ingestion; and b) after ingestion by a patient with a gastric pH of 2.5 or less, said gastric pH rises to at least 3.5 within 45 minutes and remains at or above 3.5 for at least 16 hours.

8. The pharmaceutical composition of claim 7, wherein said gastric pH rises to at least 3.5 within 30 minutes after ingestion and remains at or above 3.5 for at least 24 hours.

9. The pharmaceutical composition of claim 1, wherein said ppi is present in said dosage form at 1-200 mg and is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole and rabeprazole.

10. The pharmaceutical composition of claim 1, wherein said ppi is selected from the group consisting of: omeprazole, present in said dosage form at between 5 mg and 50 mg; esomeprazole, present in said dosage form at 5-100 mg; lansoprazole, present in said dosage form at 15-150 mg; pantoprazole, present in said dosage form at between 10 mg and 200 mg; and rabeprazole, present in said dosage form at between 5 mg and 100 mg.

11. The pharmaceutical composition form of claim 1 , wherein said H2 blocker is present in said dosage form at 1-300 mg and is selected from the group consisting of: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine.

12. The pharmaceutical composition form of claim 11, wherein said ppi is present in said dosage form at 1-200 mg and is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, tenatoprazole and rabeprazole.

13. The pharmaceutical composition of claim 12, wherein said ppi is selected from the group consisting of: omeprazole, present in said dosage form at between 5 mg and 50 mg; esomeprazole, present in said dosage form at 5-100 mg; lansoprazole, present in said dosage form at 15-150 mg; pantoprazole, present in said dosage form at between 10 mg and 200 mg; and rabeprazole, present in said dosage form at between 5 mg and 100 mg.

14. The pharmaceutical composition of claim 5, wherein: a) said ppi is selected from the group consisting of: omeprazole, present in said dosage form at between 5 mg and 50 mg; esomeprazole, present in said dosage form at 5-100 mg; lansoprazole, present in said dosage form at 15- 150 mg; pantoprazole, present in said dosage form at between 10 mg and 200 mg; and rabeprazole, present in said dosage form at between 5 mg and 100 mg; and b) said H2 blocker is selected from the group consisting of: cimetidine present in said dosage form at 100 to 800 mg; ranitidine present in said dosage form at 50-300 mg; famotidine present in said dosage form at 5-100 mg; ebrotidine present in said dosage form at 400 - 800 mg; pabutidine present in said dosage form at 40 mg; lafutidine present in said dosage form at 5-20 mg; and nizatidine present in said dosage form at 50-600 mg.

15. The pharmaceutical composition of claim 14, wherein said gastric pH rises to at least 3.5 within 30 minutes after ingestion and remains at or above 3.5 for at least 24 hours.

16. The pharmaceutical composition of claim 1, wherein said dosage form is a tablet, capsule or powder and wherein said ppi and said H2 blocker are in admixture.

17. The pharmaceutical composition of claim 1, wherein said dosage form is a tablet and wherein essentially all of said ppi is in one layer and essentially all of said H2 blocker is in a separate layer.

18. The pharmaceutical composition of claim 17, wherein the layer containing said ppi and/or the layer containing said H2 blocker also comprise at least one disintegrant and/or a compound that causes effervescence.

19. The pharmaceutical composition form of claim 17, wherein said dosage form comprises a disintegrant selected from the group consisting of: croscarmellose sodium, crospovidone, sodium starch glycolate, povidone, crosslinked polyvinylpyrrolidone, starch, low substituted hydroxymethylcellulose, methylcellulose, microcrystalline cellulose.

20. A method of treating a patient for a disease or condition characterized by abnormal gastric acid production comprising administering to said patient the pharmaceutical composition of any one of claims 1-19.