GB2330305A - Pharmaceutical composition for the treatment of peptic ulcers - Google Patents

Abstract

A phytochemical composition comprising an extract of Indigofera arrecta plant leaves, wherein said extract is prepared using a suitable solvent, is used for the management and treatment of peptic ulcer conditions and is preferably formulated as a capsule. The method of preparing said extract comprises pulverisation of the leaves and extraction using a suitable solvent such as hot water.

Description

PRARNIACEI,TICAL COMPOSITION FOR THE MANAGEMENT OF PEPTIC ULCER CONDITIONS BACKGROUND OF THE AN-ENTION This invention relates to a pharmaceutical composition for managing peptic ulcer conditions comprising an extract of Indiootera arrecta, and to methods of preparing the extract.

Peptic ulcer has been defined as a benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin. It is a gastro-intestinal problem that is prevalent in society.

The occurrence of the disease has been associated with over-indulgence, inappropnate habits. anxiety and stress. Considerable energy and resources have been expended towards relieving symptoms of peptic ulcer which usually manifests as an excruciating pain, especially in the upper abdomen.

For centuries neutralization of gastric acid secretion with antacids and H2receptor antagonists, provided the only relief from the pains of peptic ulcer.

These drugs are generally expensive. Consequently, the socio-economic impact of peptic ulcer disease on society can only be imagined.

In the foregoing assertion, efforts have been made to find a suitable palliative andior curative agent for the treatment of peptic ulcer conditions frorr, medicinal plants.

It is estimated that approximately 1070 of most populations globally will develop severe peptic ulcer conditions at some time during their lifetime.

The lesions occur at all ages and affect both sexes.

Authorities estimate that at least five million people suffer from active peptic ulcers each year, and approximately 350,000 to 500,000 new cases are diagncsed annually in the United States of Ninerica alone. More than 600,000 patients are hospitalized in the US each year for severe episodes.

In approximately one-third of these cases serious complications occur, including intestinal obstruction, upper gastrointestinal haemorrhage and perforation. Furthermore, each year, over 6.000 deaths in the US are directly caused by ulcer disorder. In addition, peptic ulcer conditions have been implicated as an indirect contributing factor in an additional it 000 deaths each vear.

In Nigeria, peptic ulcer conditions general afflict persons between the ages of 21 and 51. Duodenal ulcers have their greatest Impact in middle age while gastric ulcers become increasingly more frequent with advancing age.

Peptic ulceration reflects on imbalance between the aggressive action of acid peptic secretions and the defensive forces that protect the mucosa. Gastric ulcers result from lowered defensive mechanisms and duodenal ulcers are the consequence of the destructive action of increased acid-peptic secretions.

Duodenal ulcers occur when gastric mucosa secretes substantial amounts of acid. Although some patients with duodenal ulcers have normal levels of acid secretion, on the average they are hyperchlorhydric. Gastric acid has two phases, viz; (1) a cephalic phase (vagally mediated) in which direct cholinesgic stimulation of parietal cells induces gastrin release from the antrum, and (2) a less powerful antral phase when food enters the stomach, causing liberation of more gastrin from the antral mucosa.

Evidence that patients with duodenal ulcers have increased parietal cell mass also suggests a genetic predisposition even though experimental data indicate that parental cell hyperplasia can be acquired.

Gastric ulceration results from lowering of the gastric mucosal resistance.

Principal among the defensive influences is mucous secretion. The increased frequency of gastric ulcers with advancing age might be compatible with progressive inability to secrete a protective layer of mucous Chronic gastritis is a frequent concomitant of gastric ulcer is associated with impaired mucous secretion and is also age-related. In experunental animals, it has been demonstrated that protein depletion, avitaminoses and general malnutrition increase the susceptibility to gastric ulceration.

There is now growing evidence that Helicobactor pviori, a bacterium, may be the cause of duodenal ulcer. The evidence linking Helicobactor pylori with benign gastric ulcer is less convincing than duodenal ulcer. However, the consensus now is that the organism is probably important in the pathogenesis of 70% of gastric ulcers not attributable to the use of nonsteroidal anti-inflammatorv drugs (NSAIDs).

The symptoms evoked by peptic ulcers are exceedingly variable; some ulcers being virtually asymptomatic. Nausea and vomiting may be produced by either duodenal or gastric ulcers, but particularly by the latter. The most consistent manifestation is epigastric pain described variably as burning gnawing or boring. Classically, the duodenal ulcer pain becomes most severe two or three hours after the last meal and persists until it is relieved by food or antacids. For this reason, the pain recurs in the middle of the night and requires a glass of milk or antiacid for its relief. Such episodic pain may last for weeks or months only to abate, usually with regulated dietary regimen and therapy. Recurrence is often trlggered by dietary indiscretions or stress and is usually very, rapid and sometimes dramatic, presenting with haemorrhage or perforation. Death from peptic ulcer is usually due to bleeding or perforation. In addition, a high proportion of patients who die or whose ulcers bleed or perforate have no warning signals.

SUMMARY OF THE INVENTION According to a first aspect of the invention there is provided a pharmaceutical composition for managing peptic ulcer conditions comprising an extract of Indisofera arrecta (family Papilionaeeae), preferably Indiaofea arrecta plant leaves, the extract having been prepared using a suitable solvent.

The solvent is preferably water, more preferably hot water.

The solvent extract is preferably freeze-dried before used.

The pharmaceuticai composition of the invention may include as an excipient for oral administration, a combination of magnesium carbonate, generally heavy magnesium carbonate, a starch, for example dried maize starch, talc and magnesium stearate. In a preferred form, the pharmaceutical composition of the invention comprises about 8 parts to about 12 parts by weight of the extract, about 170 parts to about 180 parts by weight of magnesium carbonate, about 100 parts to about 120 parts by weight of a starch, and about 4 parts to about 6 parts by weight of a mixture of talc and magnesium stearate.

The pharmaceutical composition of the invention preferably comprises about 2,6% to about 4.35 by weight of the extract by total weight of the composition.

The pharmaceutical composition of the invention is preferably formulated as a capsule.

According to a second aspect of the invention there is provided a method of preparing an extract of Indiaofera arrecta, including the steps of: (i) reducing Indioofera arrecta plant material to a powder; and (ii) subjectina the powder to an extraction process using a suitable solvent.

The method of the invention may include an additional step of: (lii) freeze-drning the solvent extract.

The pharmaceutical composition of the invention is of particular use in the management of peptic ulcer conditions.

DESCRIPTION OF ENIBODDIENTS In accordance with the invention, a pharmaceutical composition for treating and managing peptic ulcer conditions in humans is provided. The composition Is prepared by extracting effective peptic ulcer inhibiting chemicals from the powdered leaves of Indiaofera arrecta plant. In a preferred form of the invention, the powdered leaves are subjected to a hot water extraction process whereby the powdered leaves are contacted by hot uater for a period of hours. The extract may be combined with an excipient carrier material to prepare an admixture which may be encapsulated for oral administration. The admixture, which may preferably contain from about 2,6 to about 4.3 % of the extract by weight, is preferably administered orally to a human patient afflicted by a peptic ulcer condition.

To prepare the extract, the leaves of Inditofera arrecta plant are dried and reduced to a fine powder by grinding with a mortar and pestle or ball mill.

500 grams of the finely ground material are then macerated in 3 litres of water and heated over a boiling water bath for about 4 hours. The resultant mixture is then filtered using filter paper and the filtrate is concentrated in vacuo to a volume of about 800 ml. The concentrate is then freeze-dried for about 48 hours using a Finn - Aqua Lyovac freeze dryer to provide a dry powder containing the active drug materials extracted from the initial powdered leaf material. The typical yield of the extracted material is about 14 to 1570 based on the original weight of the crude ground leaf material.

That is to say. the yield is about 70 to 75 grams when the starting batch is about 500 grams.

Phytochemical screening of the crude ground leaf material revealed the presence of volatile oils, saponins, tannins and resins. However, only tannins and saponins were found to be present in the freeze dried extract.

Glycosides. anthraquinones, alkaloids, hydrolysable tannins and resins were all absent from the freeze-dried extract. The freeze-dried extract contains about 0,02 to 0,04cm by weight of volatile oils and about 7 to 9% by weight of tanruns.

The fndiaofera arrecta plant was selected as a possible candidate for scientific investigation in the first place and its effectiveness against bacteria known to be associated with peptic ulcer conditions was evaluated using the freeze-dried extract. The minimum inhibitory concentration and minimum bactericidal concentration of Indigofera arrecta extract against Ps. Aeruoinosa. E. Cold. S. Aureus and B. Subtilis were determined using the agar dilution method. Indi ofera arrecta extract showed potent antimicrobial efficacy against all of the tested commonly encountered microbes. The minimum inhibitory concentrations were Ps. Aeruainosa, 0,5 mg?ml; E. Coli, 1 mg ml; S. Aureus, 1 mg/ml; and B. Subtilis, 1 mg.'ml. The minimum bactericidal concentrations were 1 mg/ml for Ps. Aeruoinosa and 2 mg/mi for the other three bacteria species.

The freeze-dried extract of Indityofera arrecta leaves was subjected to acute toxicity testrng by the intraperitoneal route in mice using standard procedures. No remarkable adverse effect was observed. The LD50 was established as 245 > 28 mg/kg i.p.

The target system in peptic ulcer disease is the gastrointestinal tract. Many anti-ulcer agents, especially those that interact with receptor systems, influence gastrointestinal physiology and its response to ulcerogemc substances. Based on this premise, the effect of the freeze-dried hot water extract of Indigofera arrecta leaves and its interaction with acetwlcholine (Ach) and histamine were investigated on both smooch muscles and skeletal muscles. The results indicate that the extract of Indiaofera arrecta leaves rnav contain some anti-spasmodic principles which relax the smooth muscles of the gastrointestinal tract.

In a preliminary study, the aspirin model of inducing experimental gastric ulcer in rats was used to assess the anti-ulcer activity of the extract of Indigofera arrecta leaves which is the subject of the invention. As shown in Table !, the extract of Indigofera arrecta leaves has a remarkable effect against aspirin-induced ulcers. This effect increased with the dose of the extract as shown by the mean ulcer indices.

TABLE I

Dose of I. arrecta Extract Ulcer Index Normal saline solution 1,1 # 0,07 250mg of extract'ml of saline 0,5 + 0,12 500mg of extractZml of saline 0,24 1 0 02 Drugs that delay the small intestinal transit time have beneficial effects on ulcer patients. The effect of the Indigofera arrecta extract on small intestinal transit in mice was tested using the charcoal meal method. The results in Table II below show that intraperitoneal administration of the extract in mice significantly reduced small intestinal transit. The inhibition, however, did not seem to be dose-dependent.

TABLE II

Dose of Extract % Distance % Inhibition Travelled Normal saline solution 92,38 # 8,8 7.4 250mg/ml of saline 33,93 + 1,2 66,07 500mg/ml of saline 61,16 # 11,3 38,8 Noradrenaline 64,6 + 9 0 35,4 The Indizofera arrecta extract of the invention showed little tendency to induce inflammation. In fact, during testing the extract was administered l.p (900 mg kg) for 1 hour before inflammation was induced. On the other hand, the Indioofera arrecta extract at the dose tested did not exhibit potent anti-inflammatory activity. Significant (P < 0,05) anti-inflarnrnatory activity was observed. however, 80 minutes after egg-albumin.

The analgesic effect of the Indiaofera arrecta extract of the invention was tested in thermal pain (hot plate at 50,2 + 1 C) and chemical pain (ace:ic acid induced writhing). In the two models, it appeared that the Indiaofera arrecta extract was ineffective in increasing the pain threshold.

Antisecretory activity of the Indioofera arrecta extract of the invention was also studied. This study was performed in pylorus - ligated (shay) rats.

After 48 hours fasting with access to water ad libitum. the pylorus was ligated under pentobarbitone anaesthesia. Pylorus ligation of the rats for 6 hours caused accumulation of gastric secretory volume and increased gastric acid ourput. As shown below in Table III, the Indigofera arrecta extract of the invention significantly decreased the volume and acidity of basal gastric secretions. The number and severity of ulcers were remarkably reduced in animals treated with the Indigofera arrecta extract of the invention.

Nioreover, it was determined that the effect of the extract was dose dependent.

TABLE III

Treatment Dosage/Kg Volume of Acid Output Gastric Secretion (mEq/L) 40ml saline 3.6 . 0,19 250 1 16,4 50mg I. arrecta extract 2,6 # 0,99 170 # 6,8 100mg I. arrecta extract 2,3 + 0,12 150 1 8.2 The Indigofera arrecta plant leaf extrac: of the invention was standardised and formulated into capsule dosage forms using World Health Organisation (,VHO) guidelines. These guidelines clearly advise that when a plant based product e.g. herbal medicine) is safe and indicates efficacy, it can be subsequently standardised and formulated into suitable dosage for clinical trials In accordance with accepted procedures it has been determined that an appropriate daily dosage of the Indizofera arrecta plant leave extract of the present invention is approximately 3 mg/kg of body weight administered orally in two divided doses.

Clir,ical trials for the Indigofera arrecta leaf extract of the invention commenced using volunteers. The clinical parameter of episodic pain, nausea and vomiting as well as kidney and liver haematological status and function were assessed. The data obtained so far indicates the efficacy of the Indigofera arrecta plant leaf extract against peptic ulcers with no detectable adverse effects on kidney, liver and blood chemistry. The values recorded for these parameters fall within normal ranges. On the average about 807a of those in the test groups have experienced relief from episodes of pain smce they entered the test program.

As a result of the testing to date, it has been determined that an appropriate and effective formulation of the Indioofera arrecta plant leaf extract of the invention for oral administration to humans for managing peptic ulcer conditions includes about 8 parts to about 12 parts by weight of the extract itself, about 170 parts to about 180 parts by weight of heavy magnesium carbonate, about 100 parts to about 120 parts by weight of dried maize starch and about 4 parts to about 6 parts by weight of a mixture of talc and magnesium stearate. This formulation is prepared by adsorbing about 200 mg of the freeze-dried extract, which is a sticky solid mass, in about 20 to 25 ml of methanol. The mixture is subjected to evaporation over a water bath leaving a thick liquid mass. About 3 to 4 grams of heavy magnesium carbonate is added as an agent for adsorption, after which the mixture is triturated to present a homogenous mass. About 2 to 2,4 grams of dried maize starch is then added and the mixture again triturated to form a uniform mixture. About 8 to 12 mg of a talc/magnesium stearate mixture is then added and again the mass is mixed until uniform. The material is then filled into capsules such that each capsule contains from about 282 to 306 mg of the uniform mixture. The daily dose of the Indigofera arrecta plant leaf extract of the invention is then administered orally as two separate capsules, preferably one in the morning at breakfast time and the other in the evening before bed time.

Claims (14)

1. CLAIMS 1A pharmaceutical composition for managing peptic ulcer conditions comprising an extract of Indiaofera arrecta, the extract havwg been prepared using a suitable solvent.
2. 2 A pharmaceutical composition according to claim 1 comprising an extract of Indioofera arrecta plant leaves.
3. 3 A pharmaceutical composition according to claim 1 or claim 2 wherein the solvent is water.
4. 4 A pharmaceutical composition according to claim 3 wherein the solvent is hot water.
5. 5 A pharmaceutical composition according to any one of claims 1 to 4 wherein the solvent extract is freeze-dried.
6. 6 A pharmaceutical composition according to any one of claims 1 to 5 comprising as an excipient for oral administration magnesium carbonate, a starch, talc and magnesium stearate.
7. 7 A pharmaceutical composition according to claim 6 wherein the composition comprises about
8. 8 parts to about 12 parts bv weight of the extract, about 170 parts to about 180 parts by weight of magnesium carbonate, about 100 parts to about 120 parts by weight of a starch and about 4 parts to about 6 parts by weight of a mixture of talc and magnesium stearate.

   S A pharmaceutical composition according to any one of claims 1 to 6 comprising about 2,6% to about 4,3% by weight of the composition of the extract.
9. 9 A pharmaceutical composition according to any one of claims 1 to 8 formulated as a capsule.
10. 10 A method for preparing an extract of Indi(Jofera arrecta comprising the steps of: (i) reducing Indigofera arrecta material to a powder; and (ii) subjecting the powder to an extraction process using a suitable solvent.
11. 11 A method according to claim 10 wherein in step (i) the Indiaofera arrecta material is Indiaofera arrecta plant leaves.
12. 12 A method according to claim 10 or claim 11 wherein in step (ii), the solvent is water.
13. 13 A method according to claim 12 wherein in step (ii) the water is hot water.
14. 14 A method according to any one of claims 10 to 13 which includes the step of (iii) freeze-drying the solvent extract.