GB2368013A

GB2368013A - Antacid composition

Info

Publication number: GB2368013A
Application number: GB0104012A
Authority: GB
Inventors: Richard Orlando Brown
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-02-19
Filing date: 2001-02-19
Publication date: 2002-04-24
Anticipated expiration: 2021-02-19
Also published as: GB2368013B; GB0104012D0

Abstract

An antacid composition capable of neutralising gastric acid comprises (a) xantham gum, (b) an effective amount of oxethazaine capable of alleviating pain associated with peptic ulcers and (c) the acid neutralising agents, aluminium hydroxide, magnesium hydroxide and magnesium trisilicate, respectively. Such compositions may be used to treat conditions.

Description

NEUTREENA A discussion of the prior art ANTACIDS are pharmaceutical preparations used to anticipate and manage pain associated with peptic ulcers and hyper-secretion of gastric acid by the neutralisation of gastric acid.

They are also employed as home remedies in conditions affecting the stomach, which may not necessarily be related to hyperacidity. The agents do not act by reducing the volume of hydrochloric acid secreted, but rather by increasing the gastric pH they diminish the activity of pepsin in the gastric secretion.

Basic metal salts and their use in antacid formulations are known in the art. Examples of metals known to form basic salts are alkali or alkaline earth metals and aluminium. The most commonly employed aluminium salts are the hydroxide, carbonate or phosphate.

Examples of alkaline earth metals such as calcium are known, the use calcium carbonate as an antacid either alone or in combination with other metal salts, such as magnesium carbonate and magnesium hydroxide are known. Antacids may be placed in two main groups depending on the extent-of absorption of the salts formed into the systemic circulation and the resultant increase in blood and urine pH. Examples of systemic and nonsystemic antacids are sodium bicarbonate and magnesium hydroxide, respectively.

Various combinations of antacids exist with the aim to reduce adverse effects associated with antacid administration and improving their therapeutic effectiveness. For example, many antacid products contain both magnesium and aluminium, combining slow-acting aluminium hydroxide with fast acting magnesium hydroxide. The aluminium hydroxide in such formulations also counters the laxative action of magnesium hydroxide. However, prolonged use of such preparations may cause hypermagnesemia and hypophosphatemia.

Other formulations contain simethicone, which is an inert polymer that produces an antiflatulent effect. Various agents including oxethazaine have also been used to minimize

the reflux of gastric acid into the esophagus. zn Although intensive antacid therapy has been shown to be less expensive and as effective as the H2 antagonists and sucralfate, it is uncommon to use antacids solely for the treatment of peptic ulcer due to the inconvenience of the regimen, palatability, and the adverse effects associated with antacid administration. It is the object of this invention to address all the inadequacies associated with the use of antacids. (Textbook of Therapeutics Drug and Disease Management: -469; Extra Pharmacopoeia Martindale, 31st Edition: -1191-1192 ; Human Pharmacology Molecular to Clinical :-795-796) Antacids are therapeutically effective only when present in the stomach, consequently therapeutic effectiveness depends to a great extent on the rate of gastric emptying. The bicarbonates of sodium and potassium have a rapid onset of action, but a short duration of action. The carbon dioxide produced from the reaction of the bicarbonates is a potent stimulant for gastric acid secretion, causing an undesirable acid rebound effect. Magnesium hydroxide has a rapid onset of action, with a resultant increase in gastric pH between 8 and 9. In contrast, magnesium trisilicate and aluminiumhydroxide react slowly to neutralize gastric acid and have a slow onset of action.

Aluminium Hydroxide-This compound has found use as an antacid. Aluminium hydroxide adsorbs and temporarily inactivates pepsin, which may contribute to the healing of peptic ulcers. It has a slow onset of action and neutralizes gastric acid, with a resultant increase in gastric pH. It is also known to delay gastric emptying.

References : Comprehensive Pharmacy Review, 3rdEdition pg. 549 Drug Evaluations Annual 1994, pg. 908 Martindale : The Extra Pharmacopoeia, 31stEditionpage 1203-1204.

Magnesium Hydroxide-This compound has found use as an antacid and an osmotic laxative. Magnesium hydroxide reacts with gastric acid to form magnesium chloride, an absorbable compound that exerts a cathartic effect. When compared to sodium bicarbonate and calcium carbonate its onset of action is nearly as prompt and complete, however producing minimal systemic effect when compared to the former. It has a delayed action, as some of the compound that does not react at the time of administration may react with subsequently secreted gastric juice, this property is however dose related.

References : Comprehensive Pharmacy Review, 3rdEdition pg. 549 Drug Evaluations Annual 1994, pg. 908-909 Martindale : The Extra Pharmacopoeia, 31stEditionpagel226.

Magnesium Trisilicate-is also used as an antacid and an adsorbent. However, this compound must first undergo hydrolysis before it can exert its acid neutralising action. The antacid action is exerted slowly, and hence it does not give quick symptomatic relief as the alkali carbonates, bicarbonates and oxide. However, its action is prolonged and hence is useful in the management of gastric and duodenal ulcer.

References : Comprehensive Pharmacy Review.. Edition pg. 549 Drug Evaluations Annual 1994, pg. 908 Aartindale : The Extra Pharmacopoeia, 37Edition page 1226. Oxethazaine-This is a local anesthetic that has a prolonged anesthetic effect on the gastro-duodenal mucosa and is also poorly absorbed from the mucosa.

ReferencM.'M/dale : The Extra Pharmacopoeia, J/tEdition page 1337.

Problems to be solved 1. The symptomatic management of pain associated with peptic ulcer disease.

2. The influence of the aggressive factors such as pepsin, gastric acid and bile on the t : p damaged gastrointestinal mucosa.

3. The inconvenience of antacid regimen.

4. The systemic effects associated with prolonged antacid use.

5. The gastrointestinal adverse effects associated with antacid administration.

The approach to symptomatic management of pain from the position of the prior art was simply based on the frequent administration of large or sufficient quantities of acid neutralising agents. However, the frequency of administration required to alleviate pain has proven to be too burdensome to patients. It is also known that the perception of pain does not always correlate with the presence or absence of acid or ulcer craters. According to Isenberg, (1982) there is a poor correlation between ulcer healing and the disappearance of pain with antacid therapy. The precise mechanism by which antacids alleviate pain in

peptic ulcer disease is also unknown. (Extra Pharmacopoeia Martindale, 37 Edition :1191 ; Pharmacotherapy A pathophysiologic approach :-704 ; Drug Evaluation wnual 1994 :-90./) From the above stated inadequacies it became clear to the inventor, that symptomatic pain management by using acid neutralising agents as the sole agents of therapy is insufficient.

Since the management of pain is symptomatic, the author concluded that the use of a localmucosal anesthetic in conjunction with a sufficient quantity of acid neutralising agents would yield better results. Although, a local-mucosal anesthetic has been used in antacid formulations before the purpose of its inclusion was however different. According to US Patent number 525491, oxethazaine, which is a local-mucosal anesthetic, has been used before in an antacid formulation for treating gastro esophageal reflux.

Abstract from application for US Patent-525491.. Pharmaceutical composition for treating-astro esophageal reflux.

A pharmaceutical composition comprising (1) Oxethazaine in an amount sufficient to indirectly inhibit relaxation of the lower esophageal sphincter by acting on mechanoreceptors located in the fundus of the stomach and (2) a carrier for the said oxethazaine selected from the group consisting of alginic acid and alginates.

Summary In a particular aspect this invention relates to gastro-esophageal reflux (heartburn). In some humans, the lower oesophageal sphincter is prone to relaxing more frequently than in other humans. As a consequence gastrointestinal fluid can pass into the esophagus at suchtimes as the lower oesophageal sphincter is relaxed so causing the burning pain.

Our research has shown that if a local anesthetic is applied to the gastric mucosa below the lower oesophageal sphincter the frequency of relaxation can be materially reduced.

However, a major delivery problem is to obtain contact of the local anesthetic with the gastric mucosa below the lower oesophageal sphincter.

The present invention provides a pharmaceutical composition comprising a local anesthetic adapted to inhibit relaxation of the lower oesophageal sphincter and a carrier therefor comprising a material adapted to float on the gastrointestinal fluid.

End of Abstract An abstract from US Patent-525491 was provided to show that although a local anesthetic was included in that formulation the purpose of its inclusion was quite different from its intended use in the inventor's formulation.

Although significant progress has been made in the provision of mucosal protection or cytoprotection in cases where such protection is indicated, the use ofxanthan gum to provide such protection is unknown. In disorders such as peptic ulcer, duodenitis and gastritis where the gastrointestinal mucosa needs protection from the aggressive factors; such as pepsin, gastric acid and bile in order to facilitate speedy regeneration of the latter, a cytoprotective agent is indicated.

The earliest type of mucosal protection provided, included the use of extracts from mucilage producing plants, which formed a barrier between the damaged mucosa and the aggressive factors that hinder the regeneration of the latter. Some common sources of mucilage include; the dried ripe seeds of Plantago major, the dried ripe seeds of Linum usitatissimum. tragacanth gum, acacia and guar gum. (British Pharmaceutical Codex 1954) Such agents formerly known as demulcents simply formed a coat over the mucosa.

Demulcents are polysaccharides by chemical nature and are non-selective with respect to

the type of protection they offer. According to Dorland's Illustrated yvMical Dictionary, demulcents are agents that sooth; bland or allay the irritation of inflamed or abraded surfaces; a soothing, mucilaginous, or oily medicine or application.

Although this method of cytoprotection has long since been used, these agents are still being used in modem pharmaceutical preparations. One such example is the use of guar gum and other antacids for protection of the oesogastroduodenal mucous membrane. See, US Patent 4 7643 74.

However, the art of cytoprotection by non-selective coating of the gastrointestinal mucosa has improved significantly to the use of agents that bind specifically to ulcer craters. One such example of a selective cytoprotective agent is sucralfate.

Textbook of Therapeutics Drug and Disease Management --472

Pharmacotherapy A pathophysiologic approach :-699 Hillyard et al, Proc Soc Exp Bio Med 115 : 1108-1112, (1964) Extra Pharmacopoeia Martindale, 25 th Edition, 1967 The inventor's hypothesis in the publication NEUTREENA dated August 28,2000 (See the attached for reference) relating to the possible use of xanthan gum was supported by research conducted by Japanese scientists. (US Patent-5518711: X-ray contrast medium comprising barium and xanthan gum for examination of large and small intestine.)

Abstractfrom app//CMM./ < tPa ! -7777 :-A- COKM KMW CO/MpM/ barium and xanthan gumfor examination of large and small intestine.

As a result of extensive studies undertaken to seek a contrast medium equipped with satisfactory properties in respect of both coating ability and flowability the present inventors have now found that when xanthan gum is used the flowability can be significantly ameliorated while maintaining the coating ability to that attainable with gum tragacanth.

The 4 claims made on the invention: (1) An X-ray contrast medium for a double contrast enema examination of the large and the small intestine comprising an aqueous suspension containing 15 to 35 w/v % of barium sulfate and 0.15% to 0.6 w/v % of xanthan gum, wherein the barium sulfate concentration is in the range of 20 to 30 w/v %, the concentration of xanthan gum is in the range of 0.2 to 0.5 w/v %, and the barium sulfate concentration is in the range of 30 to 35 w/v %, the concentration of xanthan gum is in the range of 0.15 to 0.4 w/v %.

(2) The X-ray contrast medium as claimed in claim 1, further comprising a member selected from the group consisting of gum arabic, sodium chondroitin sulfate, and a combination thereof.

(3) The X-ray contrast medium as claimed in claim 2. wherein said gum arabic, sodium chondroitin sulfate, or a combination thereof is present in an amount of 0.5 to 2.0 w/v %.

(4) A method for improving X-ray contrast images. which comprises administering to a patient the X-ray contrast medium according to claim 1, and transmitting x-rays through the x-ray contrast medium.

End of abstract From the above abstract, special mention was made to the flowability of xanthan gum and also the similarity between the coating ability of xanthan gum and tragacanth gum, a well

know demulcent. (British Pharmaceutical Coder 1994 and Extra Pharmacopoeia Martindale, 23 h Edition) It is apparent to the author that the researchers in their bid to find a satisfactory x-ray contrast medium were unaware of the fact that they also found a good mucosal protective agent, as these two groups of agents posses similar properties. It is also clear from the claims that no protection was sought on the use of xanthan gum as a mucosal protective agent.

The problem of an inconvenient antacid regimen for the treatment of peptic ulcer disease has been known for over a half a century, yet although significant progress has been made in science and technology this problem has remained unsolved. The steps taken to resolve this problem is unclear as all the controlled studies examined have maintained the existing regimen. It is however clear that any attempt to prolong the duration of acid neutralisation beyond 4H hours is not only theoretically unsound but nonsensical, as the duration of acid neutralisation should also coincide with the patient's natural physiological demand for food.

Antacid adverse effects are problematic and contribute to noncompliance. Although sodium bicarbonate and calcium carbonate are potent antacids their adverse effects preclude their use in treating peptic ulcer disease. Systemic effects associated with the use of sodium bicarbonate include systemic alkalosis and the delivery of a high sodium load when used chronically. Systemic effects resulting from the prolonged administration of large doses calcium carbonate include, hypercalcemia, hyperphosphatemia, increased blood urea nitrogen and systemic alkalosis. These agents are known as systemic antacids because they are well absorbed from the gastrointestinal tract into the systemic circulation. In order to stem the undesirable systemic effect such as alkalosis, non-systemic antacids are administered when prolonged use of the same is indicated. Non-systemic antacids may be defined as antacids that form compounds in the intestine that are not readily absorbed, examples of non-systemic antacids include antacids which contain magnesium or aluminium, or a combination of both. However, even with the use of non-systemic antacids undesirable systemic effects have been known to occur in individuals with normal renal

function. (Extra Pharmacopoeia Martindale, 3 2Edition :-1226zand Human Pharmacology Molecular to Clinical :-793) Pharmacotherapy A pathophysiologic approach :--170 Gastrointestinal adverse effects resulting from the administration of antacid include. constipation, diarrhea, flatulence and hyperacidic rebound effect. Magnesium hydroxide can cause an undesirable increase in gastric pH with a compensatory increase in the secretion of gastric acid (acid rebound effect) and it is also known to cause diarrhea, the main dose limiting adverse effect. Consequently, magnesium hydroxide is rarely used alone in the treatment of peptic ulcer disease. Aluminium hydroxide is a weaker antacid than magnesium hydroxide, it can cause constipation and hence, when administered together with magnesium hydroxide in sufficient quantity not only reduces the likelihood of a rebound effect, but can also abates the laxative action of the latter.

Textbook of Therapeutics Drug and Disease Management :-470 Human Pharmacology ivolecular to Clinical :-796 Statement of the Obiect of the Invention 1. Therapy of peptic ulcer is aimed at relieving pain, healing of the lesion and the prevention of recurrence. Increase in the gastric acid to mucous ratio results in ulcer formation accompanied by pain (due to irritation by the acid) in the stomach, duodenum or esophagus. This may be a direct consequence of an increase in gastric acid secretion or a compromised defensive mechanism of the gastro-duodenal mucous membrane. Symptomatic pain management has long been a problem in the therapy of peptic ulcer. Epigastric pain is the classic and most frequent symptom of gastric and duodenal ulcers. Ulcer related pain in duodenal ulcer often occurs 1-3 hours after meals and is usually relieved by food, but this is variable. In the case of gastric ulcer, food may precipitate or accentuate pain. The perception of pain may not correlate with the presence or absence of acid or ulcer craters.

(Pharmacotherapy A pathophysiologic approach ;-703) Although the use of antacids in the symptomatic management of pain has long been known, this problem has essentially remained unsolved. Paradoxically, with antacids there is a poor correlation between healing and the disappearance of pain (See. Isenberg, 1982).

The following is an indication of the significance of pain in gastric and duodenal

ulcers.

Frequencies represent estimates and are categorized as being consistent frequent (+ + +), infrequent (+ +), or rare (+).

In the case of gastric ulcer ; Pain (+ + + +) Epigastric pain (+ + +) Frequently severe (+ + +) Radiation to back (++) Episodic (clusters) (+) Nocturnal (+ + +) Within 30 minutes of food (± < -) Food relief (+ +) Relieved by antacids (+ + + +).

In the case of duodenal ulcers ; Pain Epigastric (++++) Frequently severe (+ + +) Radiation to the back (+ +) Episodic (clusters) (+ + +) Nocturnal (++++) Within 30 minutes of food (+) Food relief (+ + +) Relieved by antacids (+ + + +).

(Pharmacotherapy A pathophysiological approach ; page 704.) Although, the data above implies that antacids as known in the prior art are effective in treating pain related to peptic ulcer, however this is far from the reality faced by patients being treated with antacids. As stated earlier in order for an antacid to be effective if must remain in the stomach. In a fasting state the stomach empties its contents into the duodenum as often as every 30 minutes to 1 hour, this necessitates frequent administration of antacid to buffer the constant secretion of gastric acid produced.

(Textbook of Therapeutics Drug and Disease Management ; pa-9.) Formulators have sought to resolve this problem of pain management and ulcer healing by increasing the concentration of antacid formulations. However, this has not been a very successful approach, as the rate of gastric emptying rate was not addressed.

Consequently, although the results derived from the use of such formulations have been better than that of their predecessors much of the acid-neutralizing agent is emptied from the stomach un-neutralized. (Drug Evaluation Annual 1994 ; page 909J The adverse effects associated with increased antacid concentration also give rise to an increase in adverse effects, which contribute to patient noncompliance.

It is the object of the present invention is to overcome the above-noted deficiencies in symptomatic pain management in the prior art. According to the present invention this is achieved by including in the formulation three acid neutralising agents with differences both in their onset of action and rate of acid neutralisation, and a corresponding reduction in gastric emptying rate. Magnesium hydroxide was included in sufficient quantity to provide a prompt onset of action, with a resultant rapid increase in gastric pH. However, the resultant rapid and substantial increase in gastric pH could trigger a rebound increase in gastric acid secretion. In order to solve the problem last cited aluminium hydroxide was included, which has a slower onset of action and rate of acid neutralisation. This will provide steady neutralisation of subsequently produced gastric acid. One improvement on the prior art is cited in the use of magnesium trisilicate, which has an even slower onset of action than the acid neutralising agents formerly stated, with a duration of action of about 4 hours. (Extra Pharmacopoeia Martindale 25'h Edition,-93) However, in order to achieve this end, a means was devised to solve the problem of premature gastric emptying of un-neutralised magnesium trisilicate. (Drug Evaluations Annual 1994 ; page 909) This was achieved by using an agent other than aluminium hydroxide to delay gastric emptying. Xanthan gum was employed in the formulation to add viscosity to the gastric content, hence delaying gastric emptying while providing sufficient water for the hydrolysis of magnesium trisilicate. Information of the effects of the viscosity of gastric content on gastric emptying rate may be obtained from the following reference.

(Pharmaceutics The Science of Dosage Form Design; page 146) Xanthan gum was also used for its property as a drug delivery retard system. Thus, reducing the likelihood of a rebound effect as a result of the initial rapid gastric acid neutralisation by magnesium hydroxide, by providing a timely release of the active ingredients for subsequent

neutralisation. (See, Jtingbunziauer's information brochurefor the use ofxanthan-um as a delayed delivery system for pharmaceuticals) Hence, the invention provides a timely and sustained release of acid neutralizing agents, negating the necessity for frequent administrations. With this, the invention provides a means of good pain management and better compliance. The fact that ulcer healing does not necessarily mean a disappearance of pain (See Isenberg 1982 and Pharmacotherapy A pathophysiologic approach, -704), allowed the inventor to focus on a solution to this problem. Consequently, a local-mucosal anesthetic was included in the formulation to manage symptomatic pain in conjunction with acid neutralizing agents for active ulcers and for pains that persist after ulcer healing has been confirmed.

The body has several mechanisms of protecting the gastrointestinal mucosa from endogenous and exogenous noxious agents. These defensive mechanisms include mucus secretion, bicarbonate secretion, mucosal blood flow, and epithelial cell restitution, growth and wound healing after injury. Whenever these defensive mechanisms prove inadequate the gastrointestinal mucous membrane becomes damaged. The action of the aggressive factors such as the influence of gastric acid and pepsin on the mucosa impedes the wound healing process. Consequently, methods were sought to reduce the influence of the aggressive agents. One such method of facilitating better wound healing involves the use of agents, normally from the group of polysaccharides, to form a protective layer over the gastrointestinal mucosa.

(Pharmacotherapy A pathophysiologic approach:-699, and the use of non-sulfated

polysaccharides in treating ulcers Hillyard et al, Proc Soc Exp Biol Med 115 : 1108 1112, 1964) The art of protecting the gastrointestinal mucosa has long been known. In its most primitive form, this involves the extraction of mucilage from plants that contain the same; this is followed by the oral administration of the extract. Some sources from which mucilage can be extracted include, the dried ripe seeds of Plantago psyllium, the dried ripe seed of Plantago major, the dried ripe seed of Linum usitatissimum, tragacanth gum, acacia gum and guar gum. (See, The British Pharmaceutical Codex 1954 and The Extra Pharmacopoeia Martindale, 25"'Edition, 1967) These agents were formerly known as demulcents. Mucosal protective agent or cytoprotective agent now replaces this term. (Pharmacotherapy A pathophysiologic approach;-699) The term demulcent refers to agents that sooth; bland; or allay the irritation of inflamed or abrades surfaces; a soothing, mucilaginous, or oily medicine or application. (Dorland's Illustrated Medical Dictionary) Although this method of cytoprotection is so old these agents are still being used in modem pharmaceutical preparations for the same purpose. (See. US Patent-4764374 Pharmaceutical compositions based on guar gum and other antacids for protection of the oesogastroduodenal mucous membrane) However, the art of mucosal protection by coating has progressed significantly since its inception from the use of non-selective cytoprotective agents to the use of selective cytoprotective agents. These selective cytoprotective agents show a definite affinity for coating the injured areas of the mucosa, one such example is sucralfate.

It is the object of this invention to provide gastro-intestinal mucosal protection in such cases where the defensive mechanisms of such membranes have been compromised, by using xanthan gum as a nonselective cytoprotective agent. On investigating the physicochemical properties of xanthan gum, the author concluded that the latter could also be used as a cytoprotective agent. The properties of xanthan gum that indicated that it could be used as a cytoprotective agent are; (1) its chemical nature-a high molecular weight polysaccharide that dissolves well in water, (2) the production of a viscous hydrocolloid on dissolution, (3) its resistance to enzymatic degradation, (4) its high resistance to pH variations and (5) the relatively good flowability of the hydrocolloid formed. Evidence was sought to support this assumption, by closely examining research conducted on the use of xanthan gum as a

mucosal coating agent. Special reference is made to US Patent number 5518711 : X-ray contrast medium comprising barium and xanthan gumfor examination of the large and small intestine.

Abstractfrom US Patent-5518711 As a result of extensive studies undertaken to seek a contrast medium equipped with satisfactory properties in respect of both coating ability and flowability the present inventors have now found that when xanthan gum is used the flowability can be significantly ameliorated while maintaining the coating ability comparable to that attainable with gum tragacanth.

End of abstract Although the abstract made mention of the two important property of a mucosal protective agent (coating ability and flowability), no claims were made on the use of xanthan gum as a mucosal cytoprotective agent. As a result of the direct evidence obtained from the studies conducted on xanthan gum, as an x-ray contrast medium and its physicochemical properties the latter was added to the formulation to promote better wound healing and to allay the irritation of an inflamed or abraded mucosa.

3. It is the object of this invention to prolong the duration of action of antacid in the treatment of peptic ulcer, hence promoting better patient compliance. In one study, a lowdose regimen of antacid tablets (14 tablets, 280 mEq total daily dose) was as effective as ranitidine in healing duodenal ulcers. (Berstad et al 1982) Ranitidine belongs to the pharmacological group of H2-receptor antagonist. It competitively inhibits the action of histamine, with a resultant reduction in the volume of gastric acid secreted and hydrogen ion concentration. They are generally preferred to antacids because of their convenience and general lack of side effects. Ranitidine is usually administered orally twice daily, with a duration of action of about 8 hours. (Pharmacy Study Guide and Board Review ;-567) For uncomplicated duodenal ulcers an intensive course of liquid antacid (144 mEq of acid neutralizing capacity one and three hours after meals and at bedtime) may be required

(Peterso a ;/ 7977), although considerably smaller amounts are often effective. (Drug Evaluation Annual 1994,--893) Some authorities calculate doses as mEq or mmol of acid neutralising capacity and beneficial effects are not straightforward. (Extra Pharmacopoeia Martindale, 32nd Edition:

- 77) The typical antacid regimen calls for doses 1-3 hours after meals and at bedtime. ( Comprehensive Pharmacy Review, 3rd Edition :-856) From the above stated references, it became apparent to the author that in order to improve the therapeutic effectiveness of antacids. besides a sufficient quantity of acid neutralizing agent. a sustained release system is also needed. It is important to remember that gastric acid is secreted on a constant basis and peaks between meals and at nights,

(Textbook of Therapeutics Drug and Disease Management ; 469) consequently gastric acid should to be neutralised on a constant basis or antacids should posses an adequate buffering capacity to prevent a compensatory rebound effect. In the cases presented earlier and generally, much emphasis has been placed on the acid neutralising capacity of antacids.

The author agrees that this factor is absolutely necessary, but this factor should not be viewed in isolation, as any conflict with the natural physiology of humans will produce an undesirable effect. Large doses of antacids from controlled studies have not shown significant advantages over smaller adequate doses in the treatment of peptic ulcer diseases and the frequency of administration remains the same in all cases. (See the above stated examples for reference) The fate of a large uncontrolled release of an antacid may be as follows; if the gastric emptying rate is not sufficiently delayed the antacid could be emptied from the stomach un-neutralized or if it reacts readily with gastric acid, an undesirable increase in gastric pH could occur with a resultant compensatory increase in gastric acid secretion. In both cases the result obtained is undesirable and hence the regimen using large doses of antacids is similar to that of smaller adequate doses of the same. Consequently, in order to solve the problems cited earlier using a large dose of antacid with an uncontrolled reaction with gastric acid, the author chose to use a sufficiently large dose of the acid neutralising agents but allowed a timely reaction of the same with gastric acid.

The prolonged effect of the antacid is achieved by (1) using a sustained release delivery system and (2) by delaying gastric emptying. The terms used to describe a drug delivery system that allows a timely release of the active ingredients from the drug, sustainedrelease, controlled release, slow release, delayed release and prolonged release. The termsustained release will be used to describe the above stated process. According to the prior art the methods used to achieve sustained release of active ingredients include the following ; a diffusion-controlled release system, a dissolution controlled release system, a release system controlled by ion exchange and a release system controlled by osmotic pressure. A diffusion-controlled release system is achieved by formulating the drug in an insoluble matrix. The gastrointestinal fluids penetrate the matrix and drug diffuses out of the matrix by passive diffusion and is absorbed. Alternatively, the drug particles can be coated with a polymer coat of defined thickness. Following oral administration, the fraction of the drug that dissolves in the polymer coat diffuses through an unstirred film of fluid along a concentration gradient. A dissolution controlled release system is achieved by limiting the rate of dissolution in the formulation. The Noyes-Whitney equation explicitly explains the factors affecting the rate of dissolution.

For information on the factors affecting the rate of dissolution (See, Pharmaceutics The Science of Dosage Form Design :-77, 15-1-156) Drug release controlled by ion exchange is achieved by the presence of a high concentration of appropriately charged ions in the gastrointestinal tract; the drug molecule is then exchanged and subsequent diffusion releases the drug molecules out of the resin and into the gastrointestinal fluid. Drug release controlled by osmotic pressure is achieved by coating drug particles with a semi-permeable membrane. As a result of this water is drawn into the drug particle where it dissolves the drug and the latter is pumped out as a result of an increased internal pressure within the membrane.

With reference to this formulation, one may assume that prolonged action of the active ingredients is achieved by using a typical diffusion controlled release system. However, there a fundamental differences in this formulation, which makes such a conclusion erroneous. Firstly, the active ingredients within the matrix are not intended to be absorbed and the desired reaction occurs within the matrix of the polymer. Consequently, diffusion of the active ingredients does not occur. Secondly, the matrix formed is permeable to gastric acid. Hence, once gastric acid passes into the matrix, the drug particles begin to dissolve in the medium. However, according to the Noyes-Whitney equation the rate of dissolution is inversely proportional to the thickness of the diffusion layer around the particle. The high viscosity of the matrix formed and the resultant reduction in drug particulate motion are both known to increase the thickness of the diffusion layer, thus reducing the dissolution rate. Consequently, one may conclude that the prolonged action of the formulation is dissolution controlled. The author wishes to clarify any misconception held concerning the hydrolysis of magnesium trisilicate and the dissolution of the drug particles. It is necessary to remember that the level of hydrolysis does not depend on the viscosity of the medium nor the level of particulate agitation but rather on the availability of water.

The prolonged action of the drug is also achieved by delaying the gastric emptying rate.

A delay in gastric emptying rate is achieved by using a sufficient quantity of aluminium hydroxide and the increased viscosity of the gastric content provided by the dissolved xanthan gum. This not only prolongs the duration of the acid neutralisation in the stomach but it also prevents the premature ejection of acid neutralising agents with a slow onset of action, namely aluminium hydroxide and magnesium trisilicate.

Extra Pharmacopoeia Martindale, 37t Editionr-1203-1204.

Pharmaceutics The Science of osage Form Design ;-146.

It is the object of this invention to further abate untoward systemic effects from the administration of antacids. From the position of the prior art the present invention may be classified as a non-systemic antacid. Non-systemic antacids are those containing magnesium or aluminium, or a combination of both. When non-systemic antacids react with gastric acid, soluble chlorides are formed which may be absorbed from the gastrointestinal tract. However, these chlorides react with sodium carbonate in the lumen of the intestine to form insoluble carbonates, the chlorides are also known to react with fatty acid salts in the lumen of the intestine to form, soaps that precipitate and remain in the bowel. Not all the chlorides participate in these reactions and are subsequently absorbed from the intestine. The protective barrier formed from xanthan gum in solution reduces the bioavailability of the chlorides and hence the systemic effects.

E x t r a P h a r m a c o p o e i a I A a r t i n d a I e) 3 1 5 Z E d i t i o n :-1 1 9 1-1 1 9 2 Extra Pharmacopoeia, Vartindale, 31"Edition :-1191-1192 Pharmaceutics The Science qfdosage Form Design :-146-147 It is the object of this invention to provide a formulation with minimal gastrointestinal adverse effects. From the position of the prior art a combination of magnesium and aluminium minimizes the undesirable effects that would otherwise be presented from the sole use of either of these agents. Aluminium hydroxide is known to cause constipation; its slow onset of acting counteracts the rebound and laxative effect of magnesium hydroxide.

A summary or definition of the invention The present invention relates to pharmaceutical compositions and particularly to compositions for use in the alleviation and symptomatic management of pain associated with peptic ulcer disease, in treating the hyper acidic secretions of gastric acid and related gastrointestinal irritations.

Neutreena is an antacid composition in a solid dosage form, with pharmacologically active ingredients and pharmaceutical aids. The preparation is to be swallowed intact, subsequent to which rapid disintegration will occur. Aluminium hydroxide, magnesium hydroxide, magnesium trisilicate and oxethazaine are the pharmacologically active ingredients. The preparation was designed to allow a stepwise neutralization of gastric acid, based on the relative onset of action of the agents used. Magnesium hydroxide being the first to react followed by aluminium hydroxide and finally magnesium trisilicate. Oxethazaine was added to the formulation to provide relief of pain by virtue of its anesthetic properties.

Following disintegration of the tablet in vivo, xanthan gum will dissolve in gastric juice to form a viscous body of hydrocolloid. This body of hydrocolloid will provide a matrix for the hydrolysis of magnesium trisilicate and the viscosity of the medium will provide a dissolution-controlled release system.

The prolonged action of the preparation is facilitated by two modes of action. A direct mode of action on the rate of dissolution and subsequent neutralisation of the acid neutralizing agents. As a result of this a timely and sustained release of the active ingredients is provided, hence prolonging the action of such ingredients. The prolonged action of the active ingredients is also provided by an indirect action. It is known that the rate of gastric emptying is inversely proportional to the viscosity of the gastric contents.

Consequently, the high viscosity of the stomach content, provided by the dissolved xanthan gum, will retard the rate of gastric emptying sufficiently to allow a prolonged pharmacological effect of each of the active ingredients used in the formulation. In addition to this, total hydrolysis of magnesium trisilicate and the subsequent neutralization of the same are facilitated by the delay in gastric emptying. With this action, the problem of the premature ejection of unhydrolysed magnesium trisilicate from the stomach has been solved.

References : Drug Evaluations Annual 1994, pg. 909 Jungbunzlauer's, Yanthan Gum Brochure in English ; Wain Functions/Properties

Pharmaceutics The Science ofdosage Form Design, page 146 Following dissolution of xanthan gum, the resultant hydrocolloid formed spreads evenly over the gastro-duodenal mucous membrane forming a relatively stable barrier, which protects the mucosa from the pugnacious nature of pepsin and gastric acid.

The cytoprotective nature of xanthan gum in this formulation is provided by its high resistance to variations in pH and enzymatic degradation, and the presence of the acid neutralizing agents in the hydrocolloid formed. As a direct consequence of the latter the undigested xanthan gum adds bulk to the stool. The combined effects of magnesium hydroxide, magnesium trisilicate, aluminium hydroxide and xanthan gum in the stated proportions will alleviate the untoward gastro-intestinal effects normally associated with antacid administration.

References : Drug Evaluations Annual 1994, pg. 944 The absence of bicarbonates or carbonates from the formulation and the inclusion of agents with a slow onset of action reduce the likelihood of an acid rebound effect. By virtue of the pharmacokinetics of the individual agents in the formulation, Neutreena could be further classified as a non-systemic antacid; in addition to this the protective barrier provided by xanthan gum in solution reduces the bioavailability of the formed absorbable salts, thus providing minimum systemic effects.

References : Drug Evaluations Annual 1994, pg. 944 Martindale : The Extra Pharmacopoeia, 31"Edition page 1191-1192 Pharmaceutics The Science of Dosage Form Design, page 146-147 Detailed Elaboration of All Aspects of the Invention The Formulation Aluminium Hydroxide 350 mg Magnesium Hydroxide 200 mg Magnesium Trisilicate 325 mg Oxethazaine 10 mg Xanthan Gum 125 mg Microcrystalline Cellulose 120 mg Sodium Starch Glycollate 65 mg Magnesium stearate 4 mg Total weight per tablet = 1199 mg The Theoretical Acid-Neutralising Capacity (mEq) This is defined as the number ofmilIiequavaIents (mEq) ofaIN solution ofHCl that can

be brought to a pH of 3. 5 in 15 minutes.

Calculations

From the following equations : (1) Mg (OH) 2 + 2HCl.. MgCh + 2H2O 58. 32 2 x 36. 46

(2) AI (OH) 3 + 3HCl----Aids + 3H2O 78. 0 3 x 36. 46 (3) Mg2Si30s + 4HOH -2 Mg (OH) 2 + H4Si308 2 Mg (OH) 2 + 4HC !-- 2MgCl2 + 2H20

(1) 38. 32 mg of magnesium hydroxide reacts with 72. 92 mg of hydrochloric acid to produce the corresponding salt of magnesium. Hence, 200 mg of magnesium hydroxide would react with a quantity (X) of hydroxhloric acid to produce the corresponding salt. By ratio and proportion the quantity (X) was found to be 250.07 mg of hydrochloric acid.

(2) 78.00 mg of aluminium hydroxide reacts with 109. 38 mg of hydrochloric acid to produce the corresponding salt of aluminium. Hence, 350 mg of aluminium hydroxide would react with a quantity (X) of hydroxhloric acid to produce the corresponding salt. By ratio and proportion the quantity (X) was found to be 490.81 mg of hydrochloric acid.

(3) From equation (3) 260.86 mg of magnesium trisilicate hydrolyses to produce 116.64 mg of magnesium hydroxide. Consequently, 325 mg of magnesium trisilicate

would produce 145. 32 mg of magnesium hydroxide.

However, 58. 32 mg of magnesium hydroxide reacts with 72. 92 mg of hydrochloric acid to produce the corresponding salt of magnesium. Hence, 145.32 mg of magnesium hydroxide would react with a quantity (X) of hydroxhloric acid to produce the corresponding salt. By ratio and proportion the quantity (X) was found to be 181.70 mg of hydrochloric acid.

From the above reactions, the total quantity of hydrochloric acid that reacted would be the

sum of the quantities found from equations (1), (2) and (3), respectively.

(250. 07 + 490. 81 + 181. 70) = 922. 58 mg hydrochloric acid.

One mEq ofaIN solution of hydrochloric acid is equal to 36. 46 (mg/mEq).

Consequently, the theoretical acid-neutralising capacity of the present formulation is 922. 58/36. 46 = 25. 30 mEq Balancing the Laxitive and Constipating Effects A sufficient acid neutralising quantity of aluminium hydroxide (350 mg) used in the formulation could also cause an undesirable constipating effect. In order to balance this effect the total quantity of magnesium hydroxide used in the formulation should be in close proximity in weight to the former. From the formulation 200 mg of magnesium hydroxide would be inadequate to stem the constipating effect of aluminium hydroxide, however by using a sufficient quantity of magnesium trisilicate the required balance was achieved. It is important to note that in balancing the quantity of magnesium hydroxide to aluminium hydroxide, the quantity of magnesium trisilicate should be in no way directly added to the quantity of magnesium hydroxide. One molecule of magnesium trisilicate on hydrolysis produces two moleules of magnesium hydroxide. Consequently, using ratio and proportions a quantity of magnesium trisilicate was calculated to yield 145 mg of magnesium hydroxide.

References : Comprehensive Pharmacy Review, 3rdEdition pg. 549 Drug Evaluations Annual 1994, pg. 908 Martindale : The Extra Pharmacopoeia, 37Editionpage 1203-1204.

Magnesium Hydroxide-This compound has found use as an antacid and an osmotic laxative. Magnesium hydroxide reacts with gastric acid to form magnesium chloride, an absorbable compound that exerts a cathartic effect. When compared to sodium bicarbonate and calcium carbonate its onset of action is nearly as prompt and complete, however producing minimal systemic effect when compared to the former. Magnesium hydroxide also has a delayed action, as some of the compound that does not react at the time of administration may react with subsequently secreted gastric juice, this property is however dose related.

References : Comprehensive Pharmacy Review, 3rd7tion pg. 549 Drug Evaluations Annual 1994, pg. 908-909

Martindale : The Extra Pharmacopoeia, 3? Edition pagel226.

Magnesium Trisilicate-is also used as an antacid and an adsorbent. However, this compound must first undergo hydrolysis before it can exert its acid neutralizing effect. The antacid action is exerted slowly, and hence it does not give quick symptomatic relief as the alkai carbonates, bicarbonates and oxide. However, its action is prolonged and hence is

useful in the management of gastric and duodenal ulcer.

References : Comprehensive Pharmacy Review, 3rd Etionpg. 549 Drug Evaluations Annual 1994, pg. 908 Martindale : The Extra Pharmacopoeia, 31s/Edition page 1226.

Oxethazaine-This is a local anesthetic that has a prolonged anesthetic effect on the gastro-duodenal mucosa and is also poorly absorbed from the mucosa.

References : Martindale : The Extra Pharmacopoeia. 31S/Edition page 1337.

Xanthan gum-this compound has no known pharmacological effect and consequently is classified as a pharmaceutical aid. However, its physicochemical properties make xanthan gum an essential ingredient in this formulation. Xanthan gum is a high molecular weight polysaccharide produced by the bacterium Xanthomonas campestris. It dissolves well in hot or cold water producing a highly viscous hydrocolloid at low concentration. This property is essential in facilitating rapid drug dissolution and also in the formation of a viscous body in the stomach. The viscous body produced will facilitate the formation of a drug matrix and a reduction in gastric emptying rate. The gum is also highly resistant to pH and temperature variations, and also to enzymatic degradation. The above stated properties make xanthan gum an ideal choice as a non-selective mucosal protective agent and a dissolution-controlled drug release system.

Jungbunzlauer Brochure in English on Xanthan Gum Microcrystalline cellulose-A fine odourless, crystalline powder, which consists of free flowing non-fibrous particles. It exhibits the highest capacity for compressibility of all known direct compression vehicles. Microcrystalline cellulose is chemically inert, compatible with most drugs and has disintegrating properties. This agent was included in the present formulation to provide good tablet compressibility and also to facilitate rapid tablet disintegration. (See, USP-NF) Sodium starch glycolat is produced by cross-linking and carboxymethylation of starch and a subsequent purification. Both the degree of cross-linking and the degree of substitution were optimized in order to maintain a maximum disintegration efficiency.

Sodium starch glycolate takes up to 23 times its weight in water. Consequently it has a high swelling capacity combined with high water penetration account for its high disintegration rate and effeciency.

Magnesium stearate-This agent prevents adherence of the granules to the punch faces and dies. It ensures smooth ejection from the die.

Claims

Claims 1. An antacid composition capable of neutralising gastric acid and comprising physiochemically active xanthan gum, pharmacologically active ingredients-an effective amount of oxethazaine capable of alleviating pain associated with peptic ulcers in conjunction with acid neutralising agents, an effective acid-neutralising amount of aluminium hydroxide, magnesium hydroxide and magnesium trisilicate, respectively.
2. A gastrointestinal mucosal protective antacid formulation according to claim 1, wherein xanthan gum upon contact with aqueous acid forms a gelatinous mass with the pharmaceutically active ingredients and such gelatinous mass is capable of forming a relatively stable layer over the gastrointestinal mucous membrane ; where the acid neutralising agents therein are capable of protecting the mucosa by neutralising gastric acid resulting from the back-diffusion of the same.
3. A sustained release antacid formulation according to claim 2, wherein xanthan gum on dissolution in gastric fluid forms a matrix for the active ingredients and such a matrix is capable of delaying the release of the active ingredients.

4. An antacid formulation according to claim 3, having 15.0 to 30. 0 percent by weight of aluminium hydroxide

7.5 to 30.0 percent by weight of magnesium hydroxide 20.0 to 50.0 percent by weight of magnesium trisilicate.

0. 30 to 0.90 percent by weight of oxethazaine.
4.0 to 19.0 percent by weight of xanthan gum.
5. A gastrointestinal mucosal protective antacid formulation according to claim 4, wherein xanthan gum in solution forms a gelatinous mass with the pharmacologically active ingredients and such a gelatinous mass is capable of forming a relatively stable layer over the gastrointestinal mucosa; where the acid neutralising agents therein are capable of reacting with gastric acid resulting from the back diffusion of the same.
6. An antacid formulation according to claim 5, further comprising a diluent.
7. An antacid formulation according to claim 6, further comprising a binder.
8. An antacid formulation according to claim 7, further comprising a lubricant.
9. An antacid formulation according to claim 8, further comprising a glidant.
10. An antacid formulation according to claim 9, further comprising a disintegrant.
11. An antacid according to claim 10, comprising essentially 0.350 g of aluminium hydroxide.

0.200 g of magnesium hydroxide.

0.325 g of magnesium trisilicate.

0. 010 g of oxethazaine.

0.125 g ofxanthan gum.

0.120 g of microcrystalline cellulose.

0.065 g of sodium starch glycollate ; and 0.004 g of magnesium stearate per unit dose.
12. A method for treating gastric hyperacidity comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 1.
13. A method for treating gastric hyperacidity comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 2.
14. A method for treating gastric hyperacidity comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 3.
15. A method for treating gastric hyperacidity comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 4.
16. A method for treating gastric ulcer comprising administering to the patient suffering

therefrom a gastric acid neutralising amount of a composition according to claim 1. t
17. A method for treating gastric ulcer comprising administering to the patient suffering t therefrom a gastric acid neutralising amount of a composition according to claim 2.
18. A method for treating gastric ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 3.
19. A method for treating gastric ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 4.
20. A method for treating duodenal ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 1.
21. A method for treating duodenal ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 2.
22. A method for treating duodenal ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 3.
23. A method for treating duodenal ulcer comprising administering to the patient suffering therefrom a gastric acid neutralising amount of a composition according to claim 4.
24. A method for the symptomatic management of pain associated with peptic ulcer by a dual mechanism of action comprising administering to the patient suffering therefrom a sufficient quantity of the composition according to claims, which provides a local anesthetic effect and the neutralisation of gastric acid.
25. A method of providing oesogastrointestinal mucosal protection to such patients requiring the same by administering to the patient a sufficient quantity of xanthan gum according to claims.