Pharmaceutical Compositions For The Coordinated Delivery Of Naproxen And Lansoprazole

Abstract

The present invention directed to drug dosage forms that release a Lansoprazole that raises the pH of a patient"s gastrointestinal tract, followed by a naproxen. The dosage form is designed so that the Naproxen is not released until the intra-gastric pH has been raised to a safe level. The disclosure also encompasses methods of treating patients by administering this coordinated release, gastro protective, ant arthritic/analgesic combination unit dosage form to achieve pain and symptom relief with a reduced risk of developing gastrointestinal damage such as ulcers, erosions and hemorrhages

Information

Applicants

Specification

CLIAMS:1. A pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) lansoprazole, at least a portion of which is not surrounded by an enteric coating; and (b) naproxen, wherein the naproxen is surrounded by a coating that substantially inhibits the release of the naproxen from the dosage form unless it is exposed to an environment with a pH of about 3.5 or higher; wherein the unit dosage form provides for release of the lansoprazole and the naproxen such that: i) upon introduction of the unit dosage form into a medium, at least a portion of the lansoprazole is released regardless of the pH of the medium; and ii) the naproxen is released when the pH of the environment is 3.5 or higher.

2. The pharmaceutical composition of claim 1, wherein the naproxen is present in an amount of between 200 mg and 600 mg.

3. The pharmaceutical composition of claim 1, wherein the lansoprazole is present in an amount of between 5 mg and 100 mg.

4. The pharmaceutical composition of claim 1, wherein the unit dosage form is suitable for oral administration to a patient.

5. The pharmaceutical composition of claim 1, wherein the unit dosage form is a tablet or capsule.

6. The pharmaceutical composition of claim 1, wherein the one or more layers outside of the core do not contain naproxen and are not surrounded by an enteric coating.

7. The method of claim 1, wherein the coating surrounding the naproxen substantially inhibits the release of the naproxen unless it is in an environment with a pH of 5.5 or higher.

8. The method of claim 1, wherein the unit dosage form provides for the sequential release of the lansoprazole followed by the naproxen.

9. The method of claim 1, wherein the unit dosage form is a bilayer tablet having an outer layer of the lansoprazole and an inner core of the naproxen and wherein the outer layer of the tablet is surrounded by a non-enteric film coating.
,TagSPECI:FIELD OF INVENTION
The present invention is directed to pharmaceutical compositions that provide for the coordinated release of a lansoprazole and a naproxen. The present invention further discloses a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or a pharmaceutically acceptable salt thereof, and lansoprazole, or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION
Although non-steroidal anti-inflammatory drugs are widely accepted as effective agents for controlling pain, their administration can lead to the development of gastro duodenal lesions, e.g., ulcers and erosions, in susceptible individuals. It appears that a major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients. This view is supported by clinical studies demonstrating an improvement in NSAID tolerability when patients are also taking independent doses of acid inhibitors (Dig. Dis. 12:210-222 (1994); Drug Safety 21:503-512 (1999); Aliment. Pharmacol.Ther. 12:135-140 (1998); Am. J. Med. 104(3A):675-745 (1998); Clin. Ther. 17:1159-1173 (1995)). Other major factors contributing to NSAID-associated gastropathy include a local toxic effect of NSAIDs and inhibition of protective prostaglandins (Can. J. Gastroenterol. 13:135-142 (1999) and Pract. Drug Safety 21:503-512, (1999)), which may also make some patients more susceptible to the ulcerogenic effects of other noxious stimuli.
In general, more potent and longer lasting acid inhibitors, such as proton pump inhibitors, are thought to be more protective during chronic administration of NSAIDs than shorter acting agents, e.g., histamine H-2 receptor antagonists (H-2 blockers) (N. Eng. J. Med. 338:719-726 (1998); Am. J. Med. 104(3A):565-615 (1998)). The most likely explanation for this is that gastric pH fluctuates widely throughout the dosing interval with short acting acid inhibitors leaving the mucosa vulnerable for significant periods of time. In particular, the pH is at its lowest point, and hence the mucosa is most vulnerable, at the end of the dosing interval (least amount of acid inhibition) and for some time after the subsequent dose of acid inhibitor. In general, it appears that when a short acting acid inhibitor and an NSAID are administered simultaneously, NSAID-related mucosal damage occurs before the pH of the gastrointestinal tract can be raised and after the acid inhibiting effect of the short acting acid inhibitor dissipates.
Although longer lasting agents, such as proton pump inhibitors (PPIs), usually maintain a consistently higher gastroduodenal pH throughout the day, their antisecretory effect may be delayed for several hours and may not take full effect for several days (Clip. Pharmacokinet. 20:38-49 (1991)). Their effect may be diminished toward the end of the usual dosing interval. Intragastric pH rises particularly slowly with the first dose in a course of treatment since this class of drugs is enteric coated to avoid destruction by stomach acid. As a result, absorption is delayed for several hours. Even then, some patients fail to respond consistently to drugs of this type and suffer from "acid breakthrough" which again leaves them vulnerable to NSAID-associated gastroduodenal damage (Aliment. Pharmacol.Ther. 14:709-714 (2000)).
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, indicating that there remains substantial room for improvement (N. Eng. J. Med. 338:727-734 (1998)). Thus, the addition of a pH sensitive enteric coating to an NSAID could provide additional protection against gastroduodenal damage not provided by the H2 blocker or PPI alone. In addition, although long acting acid inhibitors may reduce the risk of GI lesions in chronic NSAID users, there are questions about the safety of maintaining an abnormally elevated pH in a patient's GI tract for a prolonged period of time (Scand. J. Gastroenterol. Suppl. 178:85-92 (1990)).
Recognizing the potential benefits of PPIs for the prevention of NSAID-induced gastroduodenal damage, others have disclosed strategies for combining the two active agents for therapeutic purposes. However, these suggestions do not provide for coordinated drug release or for reducing intragastric acid levels to a non-toxic level prior to the release of NSAID (U.S. Pat. No. 5,204,118; U.S. Pat.No. 5,417,980; U.S. Pat.No. 5,466,436; and U.S. Pat.No. 5,037,815). In certain cases, suggested means of delivery would expose the gastrointestinal tract to NSAIDs prior to onset of PPI activity (U.S. Pat. No 6,365,184).
US 2010/0172983 discloses the pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or a pharmaceutically acceptable salt thereof, and esomeprazole, or a pharmaceutically acceptable salt thereof.
Attempts to develop NSAIDs that are inherently less toxic to the gastrointestinal tract have met with only limited success. For example, the recently developed cyclooxygenase-2 (COX-2) inhibitors show a reduced tendency to produce gastrointestinal ulcers and erosions, but a significant risk is still present, especially if the patient is exposed to other ulcerogens (JAMA 284:1247-1255 (2000); N. Eng. J. Med. 343:1520-1528 (2000)).
In this regard, it appears that even low doses of aspirin will negate most of the benefit relating to lower gastrointestinal lesions. In addition, the COX-2 inhibitors may not be as effective as other NSAIDs at relieving some types of pain and have been associated with significant cardiovascular problems (JADA 131:1729-1737 (2000); SCRIP 2617, pg. 19, Feb. 14, 2001); NY Times, May 22, 2001, pg. Cl)).
Other attempts to produce an NSAID therapy with less gastrointestinal toxicity have involved the concomitant administration of a cytoprotective agent. In 1998, Searle began marketing Arthrotec.TM. for the treatment of arthritis in patients at risk for developing GI ulcers.
This product contains misoprostol (a cytoprotective prostaglandin) and the NSAID diclofenac. Although patients administered Arthrotec.TM.do have a lower risk of developing ulcers, they may experience a number of other serious side effects such as diarrhea, severe cramping and, in the case of pregnant women, potential damage to the fetus.
Another approach has been to produce enteric coated NSAID products. However, even though these have shown modest reductions in gastroduodenal damage in short term studies (Scand. J. Gastroenterol. 20: 239-242 (1985) and Scand. J. Gastroenterol. 25:231-234 (1990)), there is no consistent evidence of a long term benefit during chronic treatment.

Overall, it may be concluded that the risk of inducing GI ulcers is a recognized problem associated with the administration of NSAIDs and that, despite considerable effort, an ideal solution has not yet been found. Furthermore, there is a need for a clinically effective therapy that delivers to a patient in need thereof a pharmaceutical composition in a unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and lansoprazole, or pharmaceutically acceptable salt thereof, for a duration sufficient to achieve an instar-gastric pH of about 4 or greater and a plasma level of naproxen that is efficacious.

SUMMARY OF THE INVENTION
The present invention is based upon the novel method for reducing the risk of gastrointestinal side effects in people taking NSAIDs for pain relief and for other conditions, particularly during chronic treatment. The method involves the administration of a single, coordinated, unit-dose product that combines: a) an agent that actively raises intra-gastric pH to levels associated with less risk of NSAID-induced ulcers; and b) an NSAID that is specially formulated to be released in a coordinated way that minimizes the adverse effects of the NSAID on the gastro duodenal mucosa. Either short or long acting acid inhibitors can be effectively used in the dosage forms. This method has the added benefit of being able to protect patients from other gastrointestinal ulcerogens whose effect may otherwise be enhanced by the disruption of gastro protective prostaglandins due to NSAID therapy.
In its first embodiment, the invention is directed to a pharmaceutical composition in unit dosage form suitable for oral administration to a patient. The composition contains an acid inhibitor present in an amount effective to raise the gastric pH of a patient to at least 3.5, preferably to at least 4, and more preferably to at least 5, when one or more unit dosage forms are administered. The gastric pH should not exceed 7.5 and preferably should not exceed 7.0.
Most preferably, the pharmaceutical composition of the present invention is in the form of a tablet or capsule that has: (a) lansoprazole present in an amount effective to raise the gastric pH of a patient to at least 3.5 upon the administration of one or more unit dosage forms; and (b) naproxen present in an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms.
The NSAID in the dosage form should be in a core, preferably a single core when tablets are used, that is surrounded by a coating that does not release NSAID until the pH of the surrounding medium is 3.5 or higher. In the case of capsules, there may be several cores of NSAID, i.e., there may be multiple particles, each being surrounded by a coating that does not release NSAID until the pH of the surrounding medium is 3.5 or higher. The acid inhibitor is in one or more layers outside of the core which do not contain any NSAID. These layers are not surrounded by an enteric coating and, upon ingestion of the tablet or capsule by a patient, release the acid inhibitor into the patient's stomach.
The term "unit dosage form" as used herein refers to a single entity for drug administration. For example, a single tablet or capsule combining both an acid inhibitor and an NSAID would be a unit dosage form.
A unit dosage form of the present invention preferably provides for coordinated drug release in a way that elevates gastric pH and reduces the deleterious effects of the naproxen on the gastro duodenal mucosa, i.e., the lansoprazole is released first and the release of naproxen is delayed until after the pH in the GI tract has risen. For example, a single tablet or capsule containing both esomeprazole and naproxen is a unit dosage form. Unit dosage forms of the present disclosure provide for sequential drug release in a way that elevates gastric pH and reduces the deleterious effects of naproxen on the gastroduodenal mucosa, i.e., the lansoprazole is released first and the release of naproxen is delayed until after the pH in the GI tract has risen to 3.5 or greater. A "unit dosage form" (or "unit dose form") may also be referred to as a "fixed dosage form" (or "fixed dose form") or "fixed dosage combination" (or "fixed dose combination") and are otherwise interchangeable.
In a preferred embodiment, the unit dosage form is a multilayer tablet, having an outer layer comprising the acid inhibitor and an inner core which comprises the NSAID. In the most preferred form, coordinated delivery is accomplished by having the inner core surrounded by a polymeric barrier coating that does not dissolve unless the surrounding medium is at a pH of at least 3.5, preferably at least 4 and more preferably, at least 5. Alternatively, a barrier coating may be employed which controls the release of NSAID by time, as opposed to pH, with the rate adjusted so that NSAID is not released until after the pH of the gastrointestinal tract has risen to at least 3.5, preferably at least 4, and more preferably at least 5. Thus, a time-release formulation may be used to prevent the gastric presence of NSAID until mucosal tissue is no longer exposed to the damage enhancing effect of very low pH.
One NSAID of special interest in dosage forms is aspirin which not only provides relief from pain and inflammation but may also be used in low doses by patients to reduce the risk of stroke, heart attack and other conditions. Thus, pharmaceutical compositions may contain alansoprazole in combination with aspirin in an amount effective, upon the administration of one or more unit dosage forms, to achieve any of these objectives.
As with the compositions described above the unit dosage form can be a tablet or capsule in which aspirin is present in a core and is surrounded by a coating that does not release the aspirin until the pH of the surrounding medium is 3.5 or higher. The lansoprazole is in one or more layers outside the core, which do not include an aspirin, are not surrounded by an enteric coating; and, upon ingestion of the dosage form by a patient, release the acid inhibitor into the patient's stomach. Any of the lansoprazole described herein may be used in the aspirin-containing dosage forms. In dosage forms designed for providing low dose aspirin therapy to patients, the aspirin should typically be present at 20-200 mg.
An embodiment of the present invention is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising: (a) lansoprazole, at least a portion of which is not surrounded by an enteric coating; and (b) naproxen, wherein the naproxen is surrounded by a coating that substantially inhibits the release of the naproxen from the dosage form unless it is exposed to an environment with a pH of about 3.5 or higher;
wherein the unit dosage form provides for release of the lansoprazole and the naproxen such that: i) upon introduction of the unit dosage form into a medium, at least a portion of the lansoprazole is released regardless of the pH of the medium; and ii) the naproxen is released when the pH of the environment is 3.5 or higher.
In certain embodiments, the coating surrounding the naproxen in the pharmaceutical compositions in unit dosage form disclosed herein may dissolve when the pH of the environment is 4.0 or higher, 4.5 or higher, 5.0 or higher, or 5.5 or higher. In some embodiments, the naproxen may be present in the pharmaceutical compositions in unit dosage form in an amount of between 200 mg and 600 mg. In other embodiments, the lansoprazole may be present in the pharmaceutical compositions in unit dosage form in an amount of between 5 mg and 100 mg. In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In still another embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or more layers outside of the core, wherein: i) the naproxen is present in the core; ii) the coating surrounds the core; and iii) the lansoprazole is in the one or more layers outside the core.
In an embodiment of the present disclosure, the one or more layers outside of the core do not contain naproxen and are not surrounded by an enteric coating.
In another embodiment, the unit dosage form is a bilayer tablet having an outer layer of the lansoprazole and an inner core of the naproxen and wherein the outer layer of the tablet is surrounded by a non-enteric film coating.
In other embodiments, the coating surrounding the core substantially inhibits the release of the naproxen unless it is in a medium with a pH of 4.0 or greater, 4.5 or greater, 5.0 or greater, or 5.5 or greater.
(a) orally administering to the patient lansoprazole, wherein at least a portion of the lansoprazole is not surrounded by an enteric coating, wherein the dose of the lansoprazole is effective to raise the gastric pH of the patient to at least 3.5 or higher; and (b) orally administering to the patient naproxen, wherein the naproxen is surrounded by a coating that substantially inhibits the release of the naproxen unless it is in an environment with a pH of 3.5 or higher, wherein the naproxen is released and is effective to treat the pain or inflammation of the patient.
In certain embodiments, and the pain or inflammation is due to osteoarthritis and/or rheumatoid arthritis and/or ankylosing spondylitis of the patient.
In certain embodiments disclosed herein, the coating surrounding the naproxen substantially inhibits the release of the naproxen unless it is in an environment with a pH of 4.0 or higher, 4.5 or higher, 5.0 or higher, or 5.5 or higher.
In some embodiments, the naproxen may be present in an amount of between 200 mg and 600 mg. In other embodiments, the lansoprazole may be present in an amount of between 5 mg and 100 mg.
In still other embodiments, the lansoprazole and the naproxen are delivered as a unit dosage form. In some embodiments, the unit dosage form is suitable for oral administration to a patient. In another embodiment, the unit dosage form provides for the sequential release of the lansoprazole followed by the naproxen. In yet another embodiment, the unit dosage form is a tablet. In still another embodiment, the unit dosage form is a bilayer tablet having an outer layer of the lansoprazole and an inner core of the naproxen and wherein the outer layer of the tablet is surrounded by a non-enteric film coating.
In one embodiment, the dose form is a multilayer tablet comprising at least one core and at least a first layer and a second layer, wherein: i) said core comprises naproxen, or pharmaceutically acceptable salt thereof; ii) said first layer is a coating that at least begins to release the naproxen, or pharmaceutically acceptable salt thereof, when the pH of the surrounding medium is about 3.5 or greater; and iii) said second layer comprises lansoprazole, wherein said lansoprazole is released at a pH of from about 0 or greater.
In another embodiment, the dose form provides for the release of lansoprazole at a pH of from about 1 or greater, a pH of from about 0 to about 2, or at a pH of about 2 to 4. In another embodiment, at least a portion of the lansoprazole or pharmaceutically acceptable salt thereof, is not coated with an enteric coating. In another embodiment, the first layer is an enteric coating. In yet another embodiment, the multi-layer tablet is substantially free of sodium bicarbonate. In one embodiment, the first layer begins to release the naproxen when the pH of the surrounding medium is at about 4.0 or about 4.5 or greater.

DETAILED DESCRIPTION
The term "acid inhibitor" refers to agents that inhibit gastric acid secretion and increase gastric pH. In contrast to art teaching against the use of H2 blockers for the prevention of NSAID-associated ulcers (N. Eng. J. Med. 340:1888-1899 (1999)), these agents are preferred compounds in the current invention. Specific H2 blockers that may be used include cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine or famotidine. The most preferred acid inhibitor is famotidine present in dosage forms in an amount of between 5 mg and 100 mg.
Other preferred agents that may be effectively used as acid inhibitors are the proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. Examples of particular proton pump inhibitors include omeprazole, present in unit dosage forms in an amount of between 5 mg and 50 mg; lansoprazole, present in unit dosage forms in an amount of between 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); and pantoprazole, present in unit dosage forms in an amount of between 10 mg and 200 mg. Recently, a newer class of acid inhibitor has been developed which competes with potassium at the acid pump. The compounds in this class have been referred to as "reversible proton pump inhibitors" or "acid pump antagonists" and may also be used in the present invention. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole,revaprazan and soraprazan (see WO9605177 and WO9605199). Other compounds in this group are H-335/25 (AstraZeneca, Dialog file 128, accession number 020806); Sch-28080 (Schering Plough, Dialog file 128, accession number 009663); Sch-32651 (Schering Plough, Dialog file 128, accession number 006883) and SK&F-96067 (CAS Registry no. 115607-61-9).
The pharmaceutical composition also contains a non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. The NSAID may be celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of the present invention), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, and phenylbutazone. The most preferred NSAID is naproxen in an amount of between 50 mg and 1500 mg, and more preferably, in an amount of between 200 mg and 600 mg. It will be understood that, for the purposes of the present invention, reference to an acid inhibitor, NSAID, or analgesic agent will include all of the common forms of these compounds and, in particular, their pharmaceutically acceptable salts. The amounts of NSAIDs which are therapeutically effective may be lower in the current invention than otherwise found in practice due to potential positive kinetic interaction and NSAID absorption in the presence of an acid inhibitor.
The invention includes methods of treating a patient for pain, inflammation and/or other conditions by administering the pharmaceutical compositions described above. Although the method may be used for any condition in which an NSAID is effective, it is expected that it will be particularly useful in patients with osteoarthritis or rheumatoid arthritis. Other conditions that may be treated include, but are not limited to: all forms of headache, including migraine headache; acute musculoskeletal pain; ankylosing spondylitis; dysmenorrhoea; myalgias; and neuralgias.
In a more general sense, the invention includes methods of treating pain, inflammation and/or other conditions by orally administering an acid inhibitor at a dose effective to raise a patient's gastric pH to at least 3.5, preferably to at least 4 or and more preferably to at least 5. The patient is also administered an NSAID, for example in a coordinated dosage form, that has been coated in a polymer that only dissolves at a pH of at least 3.5, preferably at least 4 and, more preferably, 5 or greater or which dissolves at a rate that is slow enough to prevent NSAID release until after the pH has been raised. When acid inhibitor and NSAID are administered in separate doses, e.g., in two separate tablets, they should be given concomitantly (i.e., so that their biological effects overlap) and may be given concurrently, i.e., NSAID is given within one hour after the acid inhibitor. Preferably, the acid inhibitor is an H2 blocker and, in the most preferred embodiment, it is famotidine at a dosage of between 5 mg and 100 mg. Proton pump inhibitors may also be used and offer advantages in terms of duration of action. Any of the NSAIDs described above may be used in the method but naproxen at a dosage of between 200 and 600 mg is most preferred. It is expected that the acid inhibitor and analgesic will be typically delivered as part of a single unit dosage form which provides for the coordinated release of therapeutic agents. The most preferred dosage form is a multilayer tablet having an outer layer comprising an H2 blocker or a proton pump inhibitor and an inner core comprising an NSAID.
The invention also provides a method for increasing compliance in a patient requiring frequent daily dosing of NSAIDs by providing both an acid inhibitor and NSAID in a single convenient, preferably coordinated, unit dosage form, thereby reducing the number of individual doses to be administered during any given period.
The term "pharmaceutically-acceptable", as employed herein, indicates the subject matter being identified as "pharmaceutically acceptable" is suitable and physiologically acceptable for administration to a patient/subject. For example, the term "pharmaceutically acceptable salt(s)" denotes suitable and physiologically acceptable salt(s).
The phrase "naproxen, or pharmaceutically acceptable salt thereof" refers to the free base of naproxen, pharmaceutically acceptable salt(s) of naproxen, and/or mixtures of the free base of naproxen and at least one pharmaceutically acceptable salt of naproxen.
The phrase "lansoprazole, or pharmaceutically acceptable salt thereof" refers to the free base of esomeprazole, pharmaceutically acceptable salt(s) of esomeprazole, and/or mixtures of the free base of lansoprazole and at least one pharmaceutically acceptable salt of lansoprazole.
In the present disclosure, each of the variously stated ranges is intended to be continuous so as to include each numerical parameter between the stated minimum and maximum value of each range. For example, a range of about 1 to about 4 includes about 1, 1, about 2, 2, about 3, 3, about 4, and 4.
The present invention is based upon the discovery of improved pharmaceutical compositions for administering NSAIDs to patients. In addition to containing one or more NSAIDs, the compositions include acid inhibitors that are capable of raising the pH of the GI tract of patients. All of the dosage forms are designed for oral delivery and provide for the coordinated release of therapeutic agents, i.e., for the sequential release of acid inhibitor followed by analgesic.
It is expected that a skilled pharmacologist may 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: Indomethacin is particularly useful when contained in tablets or capsules in an amount from about 25 to 75 mg. A typical daily oral dosage of indomethacin is three 25 mg doses taken at intervals during the day. However, daily dosages of up to about 150 mg are useful in some patients.
Aspirin will typically be present in tablets or capsules in an amount of between about 250 mg and 1000 mg. Typical daily dosages will be in an amount ranging from 500 mg to about 10 g. However, low dose aspirin present at 20-200 mg (and preferably 40-100 mg) per tablet or capsule may also be used.
Ibuprofen may be provided in tablets or capsules of 50, 100, 200, 300, 400, 600, or 800 mg. Daily doses should not exceed 3200 mg. 200 mg-800 mg may be particularly useful when given 3 or 4 times daily.
Flurbiprofen is useful when in tablets at about from 50 to 100 mg. Daily doses of about 100 to 500 mg, and particularly from about 200 to 300 mg, are usually effective. Ketoprofen is useful when contained in tablets or capsules in an amount of about 25 to 75 mg. Daily doses of from 100 to 500 mg and particularly of about 100 to 300 mg are typical as is about 25 to 50 mg every six to eight hours. Naproxen is particularly useful when contained in tablets or capsules in an amount of from 250 to 500 mg. For naproxen sodium, tablets of about 275 or about 550 mg are typically used. Initial doses of from 100 to 1250 mg and particularly 350 to 800 mg are also used, with doses of about 550 mg being generally preferred.
Other NSAIDs that may be used include: celecoxib, rofecoxib, meloxicam, piroxicam, droxicam, tenoxicam, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, or NS398. JTE-522, L-745,337 and NS398 as described, inter alia, in Wakatani, et al. (Jpn. J. Pharmacol. 78:365-371 (1998)) and Panara, et al. (Br. J. Pharmacol. 116:2429-2434 (1995)). The amount present in a tablet or administered to a patient will depend upon the particular NSAID being used. For example: Celecoxib may be administered in a tablet or capsule containing from about 100 mg to about 500 mg or, preferably, from about 100 mg to about 200 mg. Piroxicam may be used in tablets or capsules containing from about 10 to 20 mg. Rofecoxib will typically be provided in tablets or capsules in an amount of 12.5, or 50 mg. The recommended initial daily dosage for the management of acute pain is 50 mg. Meloxicam is provided in tablets of 7.5 mg, with a recommended daily dose of 7.5 or 15 mg for the management of osteoarthritis. Valdecoxib is provided in tablets of 10 or 20 mg, with a recommended daily dose of 10 mg for arthritis or 40 mg for dysmenorrhea.

Manufacturing process:
The pharmaceutical compositions of the invention include tablets, dragees, liquids and capsules and can be made in accordance with methods that are standard in the art (see, e.g., Remington's Pharmaceutical Sciences, 16.sup.th ed., A Oslo editor, Easton, Pa. (1980)). Drugs and drug combinations will typically be prepared in admixture with conventional excipients. Suitable 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. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants, preservatives, disintegrants; stabilizers; wetting agents; emulsifiers; salts; buffers; coloring agents; flavoring agents; or aromatic substances.
Enteric coating layer(s) may be applied onto the core or onto the barrier layer of the core using standard coating techniques. The enteric coating materials may be dissolved or dispersed in organic or aqueous solvents and may include one or more of the following materials: methacrylic acid copolymers, shellac, hydroxypropylmethcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosetrimellitate, carboxymethylethyl-cellulose, cellulose acetate phthalate or other suitable enteric coating polymer(s). The pH at which the enteric coat will dissolve can be controlled by the polymer or combination of polymers selected and/or ratio of pendant groups. For example, dissolution characteristics of the polymer film can be altered by the ratio of free carboxyl groups to ester groups. Enteric coating layers also contain pharmaceutically acceptable plasticizers such as triethyl citrate, dibutyl phthalate, triacetin, polyethylene glycols, polysorbates or other plasticizers. Additives such as dispersants, colorants, anti-adhering and anti-foaming agents may also be included.

EXAMPLES
The disclosure is further defined in the following Example(s). It should be understood the Example(s) are given by way of illustration only. From the above discussion and the Example(s), one skilled in the art can ascertain the essential characteristics of the disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the disclosure to various uses and conditions. As a result, the disclosure is not limited by the illustrative example(s) set forth hereinbelow, but rather defined by the claims appended hereto.

Preparation of Lansoprazole Tablets:
The formulation contained drug along with excipients such as diluents (MCC), Guidant’s (talc), Lubricants (Magnesium stearate), alkalizing agents which helps solubilize and protect lansoprazole from degradation before absorption (Sodium Bicarbonate), SLS helps in wetting of lansoprazole and super disintegrants (cross povidone, cross carmellose sodium, sodium starch glycolate) for immediate release action.All the ingredients are passed through sieve 40 and used. Preliminary formulations contained 5% of Different Super disintegrants (CP, CCS, and SSG) to select best superdisintegrant for formulation of IR tablets.
Based on disintegration times the best super disintegrant is used Immediate release tablets are prepared by direct compression technique using various concentrations of superdisintegrant and wetting agent (SLS). Cross Povidone (CP) is used in 2, 4, 6% levels and SLS is used in 1, 2, 3% levels in various combinations, All ingredients except Magnesium stearate, Talc and SLS are blended in glass mortar uniformly. After the sufficient mixing of drug as well as other components, Magnesium stearate, Talc and SLS are added and mixed for additional 2-3 minutes. Finally, the powder mixture is compressed on a tablet compression machine as per the equivalent weight using 6mm punch maintaining hardness at 4-5 kg/cm2.
Table 1: indicate the various compositions of lansoprazole
Ingredients (mg) IR1 IR2 IR3 IR4 IR5 IR6 IR7 IR8 IR9
Lansoprazole 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
NaHCO3 60 60 60 60 60 60 60 60 60
CP 2 4 6 2 4 6 2 4 6
SLS 1 1 1 2 2 2 3 3 3
Talc 2 2 2 2 2 2 2 2 2
Mg. Stearate 1 1 1 1 1 1 1 1 1
MCC 26.5 24.5 22.5 25.5 23.5 21.5 24.5 22.5 20.5
Total weight (mg) 100 100 100 100 100 100 100 100 100

Preparation of naproxen core tablets:
The formulation contained drug along with excipients such as diluents (MCC), Guidant’s (talc), Lubricants (Magnesium stearate) and super disintegrants (cross povidone, cross carmellose sodium, sodium starch glycolate). All the ingredients are passed through sieve 40 and used. Core naproxen tablets are prepared by direct compression technique using various super-disintegrants. All ingredients except Magnesium stearate and talc are blended in glass mortar uniformly. After the sufficient mixing of drug as well as other components, Magnesium stearate and talc are added and mixed for additional 2-3 minutes. Finally, the powder blend is compressed on a tablet compression machine as per the equivalent weight using 6mm punch and hardness around 5-6 kg/cm2 is maintained.
Table 2: Formulation chart of Naproxen Core Tablets:
INGREDIENT(mg) CT 1 CT 2 CT 3
Naproxen 50 50 50
CCS 6 - -
CP - 6 -
SSG - - 6
Magnesium Stearate 1 1 1
Talc 2 2 2
MCC 41 41 41
Total weight(mg) 100 100 100

Formulation of coating Solution:
Coated tablets are formulated to deliver the tablet in the intestine or when the pH of the stomach rises above pH 4 preferably over pH 5, a pH sensitive coating polymer can be used. Eudragit L100-55 powder was used as coating polymer which gets dissolved or disrupted when the pH of GIT raises over 5.5. Triethyl citrate is used as plasticizer and Iron oxide Red is used as colorant. Isopropyl alcohol and acetone mixture is used as solvent for coating.

Table 3: Coating solution:
Ingredient Amount (%w/w)
Eudragit L100-55 8
Triethyl citrate 1.4
Talc 2
Iron oxide Red 0.6
Acetone 32
Iso-Propyl Alcohol 56
Total 100

Preparation of Coating solution:
A Coating suspension was prepared using pH sensitive polymer (Eudragit L 100-55), plasticizer (triethyl citrate), Colorant (Iron Oxide red) and Solvent (Isopropyl Alcohol: Acetone; 56:32). First Eudragit is dispersed in an Isopropyl alcohol: Acetone solvent mixture. This solvent is plasticized with triethyl citrate and coloring agent was added later. The mixture was stirred for 2hrs on Magnetic stirrer to ensure sufficient plasticization of the polymer.
Coating of Naproxen core tablets:
Naproxen core tablets are coated using R & D lab coater, conventional coating pan/drum with one spray gun. The coating conditions are summarized in table 4. Tablet cores are preheated to about 40oc in the coating pan with the hot inlet air. Coating solution is sprayed on tablet bed using peristaltic pump, after spray rate is optimized. The pan was set to rotate at appropriate speed and operation was continued until required % weight increment of the tablets is reached, it is done by weighing the tablets. After coating, tablets are dried in the same pan for 5 minutes turning off the spray nozzle, gently fluidizing them with air inlet. Coating over the tablets is cured in air assisted with oven at temperatures not over 35-40 0c for 2 hours.
The tablet coating process is complex, and involves parameters such as the spray pattern, drop size, and nozzle spacing (in addition to multiple other non-spray related parameters) which must all be precisely controlled in order to ensure uniform distribution of the coating material.The coating levels are determined by amount of polymer applied. Tablets are coated to weight gain 4%, 8% and 12%, based on concentration of coating solution the formulations are named CT1(4%), CT1(8%), CT1(12%), CT2(4%), CT2(8%), CT2(12%), CT3(4%), CT3(8%), CT3(12%).

Table 4: Coating parameters
Coating Pan 4” Drum
Pan speed 16 rpm
Inlet air temperature 40-45 0C
Exhaust air temperature 30-35 0C
Coating Deposition 1.2 g/min
Distance of Spray from Pan 10cm
Amount of Substrate 10 grams of tablets
Atomizing pressure 1-1.5bars
Atomizer Nozzle diameter 1mm

In vitro dissolution studies
Lansoprazole tablets: The release rate of Lansoprazole Immediate release tablets was determined using United State Pharmacopoeia (USP) XXIV dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 ml of 0.1N HCl (pH 1.2) as a dissolution medium, at 37±0.5ºC and 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at 3, 6, 9, 12, 15, 18, 21, 24, 27, 30 minutes. The samples were filtered through a 0.45 membrane filter. Absorbance of these solutions was measured at 246nm using an UV-spectrophotometer.
Naproxen Coated Tablets:
The release of naproxen coated tablets is determined according to USP XXVII by adopting Method A (USP convention INC., 2004) in pH 1.2 and pH 6.8 buffers.
The Acid Stage was performed using 475 ml of 0.1 N hydrochloric acid placed in a USP dissolution bath equilibrated to a temperature of 37± 0.5 °C. The paddle was set at 50 rpm. Six tablets were introduced into the appara¬tus and the apparatus was run for 2 h. After the operation outlined above, aliquot of the fluid was drawn for 1, 2 hours, and the Buffer Stage was commenced.
The Buffer Stage consisted of phosphate buffer of pH 6.8, by draining all the 0.1 N HCl in the vessel and immediately placing 6.8 pH phosphate buffer Adjust the pH if necessary with 0.1N orthophosphoric acid or 0.1N sodium Hydroxide and The apparatus was operated for a further 2h. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at, 5, 10, 15, 30, 45, 60, 75, 90, 105, and 120minutes. The samples were filtered through a 0.45 membrane filter. Absorbance of these solutions was measured at nm using a UV/VIS spectrophotometer. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve.

In-Vitro Drug release profile of Tablets in capsule:
Zero size capsule containing 2 lansoprazole IR9 optimized tablets and 5 Naproxen Coated tablets is placed in dissolution apparatus USP XXVII and release studies is performed. Acid stage consists of 475ml 0.1N HCl for 2 hours at 37 ± 2 ºC at 50 rpm and Buffer stage consists of pH 6.8 phosphate buffer for next two hours at 37 ± 2 ºC at 50 rpm.The absorbance’s of drugs at respective wavelengths was observed in UV spectrophotometer and Cumulative Drug release was calculated.

TIME (min) % Cumulative Drug Release
IR1 IR2 IR3 IR4 IR5 IR6 IR7 IR8 IR9
0 0 0 0 0 0 0 0 0 0
3 3.22 31 7.24 4.02 6.63 9.05 03 8.28 11.31
6 8.28 14.18 18.23 13.66 16.10 20.78 14.66 17.13 23.75
9 27.66 33.78 43.78 33.12 38.65 48.20 321 40.82 52.25
12 57.12 720 82.20 64.28 78.22 84.36 69.82 80.28 87.36
15 69.82 88.56 91.36 77.64 90.06 94.21 83.46 92.06 98.21
18 82.46 98.42 98.25 88.12 97.82 98.30 92.31 98.02
21 94.31 97.80 98.48
24 98.40 98.10

In-Vitro drug release of coated tablets of Naproxen

Time (min) % Cumulative Drug Release
CT1 (8%) CT1 (12%) CT2 (8%) CT2 (12%) CT3 (8%) CT3 (12%)
Acid Stage 0.1 N HCl
60 0 0 0 0 0 0
120 0 0 0 0 0 0
Buffer change pH 6.8 Phosphate buffer
125 1.20 0 1.86 0 0.62 0
130 3.04 1.36 3.64 1.76 2.04 1.04
135 9.85 3.22 12.58 3.84 7.56 2.46
150 57.24 11.57 63.42 13.36 53.44 10.32
165 81.08 60.26 90.22 64.88 75.83 56.78
180 98.88 82.43 98.56 88.34 94.34 78.02
195 99.18 98.59 99.12 98.48

In-Vitro drug release of coated tablets of Naproxen CT1 (8%) –CT3 (12%)
It was found that drug release from the coated tablets was resisted for first few minutes to release only small % of drug, and after that lag-time rate of drug release increased. This can be hypothesis as, it is due to coating layer present around the core tablets; the drug release was restricted for few minutes later after the coating layer got dissolved in the medium and the drug release was rapid from there. Formulation with 12% coating has shown very slower release compared to tablets with 8% coating. The formulations of CT2 have better release rate in buffer than formulations CT1 and CT3 due to the formulation parameters where faster disintegrating agent Cross Povidone has been used.
The drug release from Formulation CT2 (8%) was 90.22% for 45 minutes and CT1 (8%) was found to release 81.08% in that same time. As per the standards coated tablets must release >80% of drug from the dosage form in 45 minutes after the buffer stage has commenced. From this dissolution data it was found that formulation CT2 (8%) have higher rate of drug release than other formulations hence it is chosen for pH sensitive coating tablet for coordinated release.

In-Vitro Drug release profile of Tablets in capsule:
The in-vitro release profile of the tablets in capsule i.e., lansoprazole IR9 tablets and Naproxen CT2(8%) was performed as per USPXXVII and found that there was no significant change in the dissolution pattern compared to individual tablets. Lansoprazole IR tablets released the entire drug in less than 15 minutes in 0.1N HCl, naproxen CT2(8%) tablets did not release naproxen in acid for 2 hours. The tablets remained intact. After medium change, in pH 6.8 Phosphate buffer naproxen coated tablets released the drug in less than 1 hour.

Documents

Orders