AU1500100A - Herbal compositions for treating gastrointestinal disorders - Google Patents

Description

WO 00/25801 PCT/AU99/00945 HERBAL COMPOSITIONS FOR TREATING GASTROINTESTINAL DISORDERS TECHNICAL FIELD This invention relates to new medicinal compositions and methods for treating 5 gastrointestinal disorders, in particular the treatment of Irritable Bowel Syndrome. BACKGROUND ART Irritable bowel syndrome (IBS) is a common functional bowel disorder accounting for a significant proportion of patients seen in gastroenterology practice.1 It is characterised by chronic or recurrent abdominal pain and disturbed defecation. 10 Studies in the U.S.A. and Australia suggest that between 10% and 20% of the population suffer from this disorder. 2,3,4,5 There is no single treatment available that is reliably effective for this condition. 6,7 Patients use a variety of approaches to assist in its management including drugs, dietary modifications, counselling, and more recently Chinese herbal medicine (CHM).

8 15 According to the fundamental principals of practice in traditional Chinese medicine, treatment should be tailored to the individual clinical presentation of patients, even though they may all have the same western medical diagnosis.8,14,15 Furthermore, treatment needs to be modified at different stages of the patient's illness or recovery. However, such an approach to treatment of disease can be cumbersome 20 and is not entirely compatible with conventional pharmaceutical and medical practice. Thus, there is a need for effective standardised Chinese herbal medicinal preparations for the treatment of gastrointestinal disorders such as irritable bowel syndrome and for appropriately rigorous clinical study design for assessing their efficacy. 25 It is an object of the present invention to ameliorate at least some of the disadvantages of the prior art therapies and methods, or at least provide useful alternatives. SUMMARY OF THE INVENTION A Chinese herbal formulation disclosed herein for treatment of gastrointestinal 30 disorders, in particular Irritable Bowel Syndrome (IBS), was compared against a placebo (made to taste, smell and look like Chinese herbs) using a randomised, double-blind, placebo controlled study design. Substitute Sheet Piih 9 MI/ATT WO 00/25801 PCT/AU99/00945 -2 According to a first aspect there is provided a composition including the herbs Ledebouriellae Sesloidis, Bupleurum Chinense, Artemesiae Capillaris, Fraxini, Plantaginis, Paeoniae Lactiflorae and Schizandrae. According to a second aspect there is provided a composition including any two 5 herbs selected from the group consisting of Codonopsis Pilosulae, Atractylodis Macrocephalae, Poriae Cocos and Glycyrrhizae Uralensis, any two herbs selected from the group consisting of Agastaches seu Pogostemi, Magnoliae Officinalis, Citri Reticulatae and Saussureae seu Vladimiriae, any two herbs selected from the group consisting of Phellodendri, Coptidis, Coicis Lachryma-jobi, Zingiberis Offinicinalis and 10 Angelicae Dehuricae, and any two herbs selected from the group consisting of Ledebouriellae Sesloidis, Bupleurum Chinense, Artemesiae Capillaris, Fraxini, Plantaginis, Paeoniae Lactiflorae and Schizandrae. According to a third aspect there is provided a composition including the herbs Codonopsis Pilosulae, Agastaches seu Pogostemi, Ledebouriellae Sesloidis, Coicis 15 Lachryma-jobi, Bupleurum Chinense, Artemesiae Capillaris, Atractylodis Macrocephalae, Magnoliae Officinalis, Citri Reticulatae, Zingiberis Offinicinalis, Fraxini, Poriae Cocos, Angelicae Dehuricae, Plantaginis, Phellodendri, Glycyrrhizae Uralensis, Paeoniae Lactiflorae, Saussureae seu Vladimiriae, Coptidis and Schizandrae. Preferably, the compositions are formulated with powdered herbs. If the 20 moisture content of the herbs is high, the herbs can be baked before being powdered by for example grinding, or by other suitable means. Even more preferred are formulations which include extracts of the herbs. For such formulations each individual herb can be extracted either with water or an organic solvent (eg. alcohol) and the extracts combined in an appropriate formulation. Alternatively all the dry herbs can be 25 combined, boiled together and then concentrated by spray drying or other means known in the art, into a dry granulated formulation. Preferably, the compositions are prepared in a capsule dosage form, however it will be understood by those skilled in the art that other dosage forms may also be suitably prepared by known methods, for example tablets, powders, pastes, liquids and 30 similar dosage forms. Also it will be understood that the compositions of the present invention may also contain one or more conventional pharmaceutically acceptable excipients, adjuvants, solvents or carriers and may also include flavours, colourings, coatings, etc. According to a fourth aspect there is provided a method of treating 35 gastrointestinal disorders including the administration to a subject requiring such WO 00/25801 PCT/AU99/00945 -3 treatment a composition according to any one of first to third aspects. Preferably, the gastrointestinal disorder to be treated is Irritable Bowel Syndrome (IBS). The treatment is preferably administered orally and may be therapeutic or prophylactic. The treatment may be delivered in a single bolus dose, 5 multiple doses or via a slow release device. The term "herb" as used herein includes the whole herb or tuber, as well as the root, stem, flower or fruit of the herb. DESCRIPTION OF THE PREFERRED EMBODIMENT In a preferred embodiment of the invention, the composition of the invention 10 includes a combination of any two herbs selected from Groups 1, 2 and 3 and any three herbs selected from Group 4, depicted in Table 5. The herbs may each be included in concentration of from 1% to 30% of the total weight of the herbal composition. In another preferred embodiment the composition of the invention includes the herbs Ledebouriellae Sesloidis, Bupleurum Chinense, Artemesiae Capillaris, Fraxini, 15 Plantaginis, Paeoniae Lactiflorae and Schizandrae, each herb included in a concentration of from 1 % to 30%, the balance being made up for example by other herbs, preferably Codonopsis Pilosulae, Agastaches seu Pogostemi, Coicis Lachryma jobi, Atractylodis Macrocephalae, Magnoliae Officinalis, Citri Reticulatae, Zingiberis Offinicinalis, Poriae Cocos, Angelicae Dehuricae, Phellodendri, Glycyrrhizae Uralensis, 20 Saussureae seu Vladimiriae and Coptidis. Although the administration of compositions including a selection of herbs from each of the four groups depicted in Table 5, or the key herbs discussed above and depicted in Table 6, are useful in the treatment of Irritable Bowel Syndrome, the synergism between all the herbs renders the administration of a combination containing 25 each of the herbs mentioned desirable. Thus, in a more preferred embodiment, the composition of the present invention includes each herb combined in the proportions given in Table 2. In addition to providing for the first time an effective and well tolerated treatment for Irritable Bowel Syndrome, the availability of the herbs and ease of formulation 30 (powdering, extraction, etc.) provides a less costly alternative medicament. The treatment may also be individualised as well as prepared as a standard formulation, making the treatment more broadly applicable and effective over both short and long term administration.

WO 00/25801 PCT/AU99/00945 -4 The invention will now be described with reference to the following examples to illustrate preferred embodiments only and does not serve to limit the invention. EXAMPLE 1. Herbs and preparation of formulations For the purpose of conducting a clinical study, all herbs were used in the dried 5 powdered form and encapsulated before administration. If sufficiently dry, the herbs were powdered using a grinder or similar device. If the moisture content of the herbs was high, the herbs were baked before being powdered. The components of the standard herbal formulation according to one embodiment of the present invention are listed in Table 1. The key herbs are listed in 10 Table 2 and the grouping of the herbs for a particular selection according to one embodiment of the present invention is shown in Table 3. The placebo preparation was prepared and encapsulated by a pharmaceutical contractor. It was designed to taste, smell and look like a Chinese herb formula and, after testing on a number of independent volunteers, it was deemed indistinguishable from raw powdered Chinese 15 herbs. The herbs may also be formulated by one of the following methods: (a) concentrating either a water or an organic solvent (eg. alcohol) extract of each herb and then combining the extracts; (b) all the raw herbs can be boiled together and then concentrated by spray drying or 20 other known methods into a dry granulated formulation. The extracts can be concentrated before or after combining and may be processed into tablets or capsules. Table 1: Standard formula (capsule ingredients) Chinese name Pharmaceutical name Powdered herb Dang Shen Codonopsis Pilosulae, radix 7% 25 Huo Xiang Agastaches seu Pogostemi, herba 4.5% Fang Feng Ledebouriellae Sesloidis, radix 3% Yi Yi Ren Coicis Lachryma-jobi, semen 7% Chai Hu Bupleurum Chinense 4.5% Yin Chen Artemesiae Capillaris, herba 13% 30 Bai Zhu Atractylodis Macrocephalae, rhizoma 9% Hou Po Magnoliae Officinalis, cortex 4.5% Chen Pi Citri Reticulatae, pericarpium 3% Pao Jiang Zingiberis Offinicinalis, rhizoma 4.5% Qin Pi Fraxini, cortex 4.5% WO 00/25801 PCT/AU99/00945 -5 Fu Ling Poriae Cocos, sclerotium (Hoelen) 4.5% Bai Zhi Angelicae Dehuricae, radix 2% Che Qian Zi Plantaginis, semen 4.5% Huang Bai Phellodendri, cortex 4.5% 5 Zhi Gan Cao Glycyrrhizae Uralensis, radix 4.5% Bai Shao Paeoniae Lactiflorae, radix 3% Mu Xiang Saussureae seu Vladimiriae, radix 3% Huang Lian Coptidis, rhizoma 3% Wu Wei Zi Schizandrae, fructus 7% 10 Table 2: Key herbs Chinese name Pharmaceutical name Powdered herb Fang Feng Ledebouriellae Sesloidis, radix 3% Chai Hu Bupleurum Chinense 4.5% Yin Chen Artemesiae Capillaris, herba 13% 15 Qin Pi Fraxini, cortex 4.5% Che Qian Zi Plantaginis, semen 4.5% Bai Shao Paeoniae Lactiflorae, radix 3% Wu Wei Zi Schizandrae, fructus 7% Table 3: Herb combinations (any two herbs from group 1 can be combined with any 20 two herbs from group 2, with any two herbs from group 3, with any three herbs from group 4) Chinese name Pharmaceutical name Powdered herb Group 1 Dang Shen Codonopsis Pilosulae, radix 7% 25 Bai Zhu Atractylodis Macrocephalae, rhizoma 9% Fu Ling Poriae Cocos, sclerotium (Hoelen) 4.5% Zhi Gan Cao Glycyrrhizae Uralensis, radix 4.5% Group 2 Huo Xiang Agastaches seu Pogostemi, herbal 4.5% 30 Hou Po Magnoliae Officinalis, cortex 4.5% Chen Pi Citri Reticulatae, pericarpium 3% Mu Xiang Saussureae seu Vladimiriae, radix 3% WO 00/25801 PCT/AU99/00945 -6 Group 3 Huang Bai Phellodendri, cortex 4.5% Huang Lian Coptidis, rhizoma 3% Yi Yi Ren Coicis Lachryma-jobi, semen 7% 5 Pao Jiang Zingiberis Offinicinalis, rhizoma 4.5% Bai Zhi Angelicae Dehuricae, radix 2% Group 4 Fang Feng Ledebouriellae Sesloidis, radix 3% Chai Hu Bupleurum Chinense 4.5% 10 Yin Chen Artemesiae Capillaris, herba 13% Qin Pi Fraxini, cortex 4.5% Che Qian Zi Plantaginis, semen 4.5% Bai Shao Paeoniae Lactiflorae, radix 3% Wu Wei Zi Schizandrae, fructus 7% 15 The concentrations of individual herbs depicted in Tables 1 to 3 may vary by about ±50%. EXAMPLE 2: Selection and recruitment of patients The majority of patients were recruited from gastroenterology units in two teaching hospitals in Sydney, Australia and through private gastroenterologists. Patient 20 screening and subsequent review occurred in these centers. Patients were further diagnosed (according to Chinese medicine principles) and then treated by Chinese medicine practitioners. All herbal medicines used were administered within standard dosage levels and are all available over the counter throughout Australia. 25 (i) Subjects Patients between the ages of 18 and 75 (inclusive) were screened by a gastroenterologist. This involved a routine clinical work-up for IBS patients with tests as determined appropriate by the specialist, including a colonoscopy or barium enema in the last five years (for 18-60yrs) or within the previous 3 years (for 61-75yrs). Patients 30 were assessed according to the Rome criteria, an established standard for diagnosis of IBS - (3 months continuous or recurrent abdominal pain/discomfort including some pain present within the last two weeks AND two of the following - altered stool frequency, altered stool form, altered stool passage, passage of mucous, and abdominal WO 00/25801 PCT/AU99/00945 -7 16 71 distension).16'17 If diarrhoea was a prominent symptom lactose intolerance was excluded (by hydrogen breath testing or over a two week lactose exclusion period). A full list of inclusion and exclusion criteria are presented in Table 4. Table 4: Inclusion and exclusion criteria Inclusion criteria Exclusion criteria 1. Age 18-75 years inclusive * Pregnancy or breast feeding 2. Colonic evaluation (colonoscopy or barium * Liver disease enema) within the previous 5 years (for 0 Medications: anticholinergics, lactulose, 18-60yrs) or within the previous 3 years smooth muscle relaxants, motility (for 61-75yrs) stimulants, antidepressants. 3. IBS by criteria: * Usage of these is accepted provided At least 3 months of continuous or recurrent patient is still symptomatic of IBS, symptoms of: medications have been used for 3 * Abdominal pain or discomfort with at least months, and effects of medications are some discomfort present within the last stable. two weeks. * Current alcoholism or drug abuse and 0 Current psychiatric illness or dementia * two or more of the following on at least 0 Allergies to food additives one quarter of occasions or days: 0 Lactose intolerance - no obvious clinical i. abdominal distension that is visible indications or felt by tight clothing 0 Inflammatory bowel disease (ulcerative ii. pain relief with bowel action colitis, Crohn's) iii. more frequent stools with onset of e Gastric and duodenal ulcers pain * Cancers of the gastrointestinal tract iv. looser stools with onset of pain 0 Celiac disease v. mucous in stools * Diabetes mellitus vi. feeling of incomplete evacuation 4. At least one marking on the Visual Analogue Scales for IBS symptoms to be at least 20mm from the 'not present' end of the scale. 5. Normal liver function tests and full blood count, urea and creatinine (within the last two weeks).

WO 00/25801 PCT/AU99/00945 -8 Written informed consent was obtained from all patients before entering the study. Patients were free to withdraw from the study at any time. (ii) Treatment schedule After initial gastroenterological screening (Week 0) all patients entered a two 5 week run-in period. A Bowel Symptom Scale (BSS) was completed at the beginning and end of the two week period to assess measurement reliability, and to account for any degree of improvement based simply on admission to the study. Patients were seen on specified days by one of three herbalists during the study period and were not permitted to change herbalist during the course of the treatment. The first consultation 10 with the Chinese herbalist occurred at Week 2, at which time the patient was randomised (by an assistant) into placebo or standard treatment groups. The patient was reviewed by the Chinese herbalist at fortnightly intervals on two occasions and then monthly intervals on two further occasions. Sixteen weeks continuous treatment was administered. All patients were reviewed by their gastroenterologist after eight 15 weeks of treatment (and precautionary liver function tests performed), and reviewed again at the end of the 16 week treatment period. Patients were closely monitored for any side effects or worsening of symptoms. Follow-up questionnaires were sent to all patients 14 weeks after completion of the treatment period. Treatment codes were only broken and revealed to patients after completion of the follow-up questionnaires. 20 (iii) Herbal preparation and dispensing All herbs and the placebo formulation used in the clinical study were supplied in the same opaque capsules. Patients in both groups were required to take the same dosage levels (5 capsules thrice daily). All patients were treated in an equivalent fashion. Compliance was assessed by an item included in the Bowel Symptom Scale 25 (BSS) and by pill count. EXAMPLE 3 Assessment and data analysis (i) The Bowel Symptom Scale (BSS) The BSS was designed as the major instrument to assess change in IBS symptoms during the course of the treatment. It consists of visual analogue scales 30 related to each individual symptom and an overall severity scale. Both patients and gastroenterologists were required to complete this scale independently at the beginning and end of the treatment period. Patients were also monitored during the course of the trial using this scale. A small number of additional items, assessing rate of stool passage and interference with life activities, and recording changes in medications WO 00/25801 PCT/AU99/00945 -9 usage and fibre consumption, were included in the BSS for all patients to complete. Tests for validity and reliability of the scale are reported below. (ii) Treatment credibility rating scale In order to assess the success of patient blinding a brief questionnaire was 5 administered regularly throughout the treatment period. This four item scale was originally used to test credibility of different forms of psychological treatment but has also been successfully used in acupuncture trials.

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20 It has been shown to have good internal consistency and test-retest reliability. Tests for reliability, internal consistency, and construct validity are also reported here. 10 (iii) Statistical analysis Pearson product moment correlation was employed in the analysis of reliability and validity data. Factor analysis was also used to determine construct validity of the credibility scale. Outcome measures with categorical responses were analysed using Chi-square and Fisher's exact tests. For the bowel symptom scales analysis of 15 variance was used to determine the differences between groups at baseline, at end of treatment and on follow-up. In each case the statistical assumptions were carefully considered, p values were all 2-tailed unless otherwise indicated, a level of significance was set at 0.05. Missing scale and item scores were not replaced. Data are presented below according to an 'intention to treat' protocol, where 20 patients who withdrew from the trial are recorded as having worsened (if appropriate) for categorical items only. Data for all other outcome measures are presented as per protocol analysis. EXAMPLE 3 Results of the study A total of 78 subjects were recruited over an 18 month period: 35 were 25 randomised into the placebo group and 43 into the standard treatment group. Fifteen patients (13%) withdrew during the four month course of the trial. A further two patients were withdrawn from the trial for commencing a variety of relevant medications during the treatment period. Patient data on entry is summarised in Table 5. Table 5: Patient population characteristics pre-treatment and mean total bowel 30 symptom scores as reported by patients and gastroenterologists at start and end of treatment period, and at a follow-up. (Standard deviation in brackets, n=subject numbers). xp<0.10, xxp<0.05, xxp<0.01, #p=0.75.

WO 00/25801 PCT/AU99/00945 - 10 Placebo Standard F statistic group group (n=35) (n=43) Characteristic Weight 72.1(12.8) 66.7(16.8) 1.27 Age 45.0(13.9) 47.6(15.1) 0.39 Gender 0.46 0.65 NS# (male:female) Baseline data Gastroenterologist 182.7(65.4) 172.2(72.6) 0.52 total BSS score Patient total BSS 191.2 (69.4) 189.7 (64.8) 0.40 score End of treatment Gastroenterologist 147.2 (86.6) 70.9 (63.2) 7.92"x total BSS score (n=30) (n=35) Patient total BSS 150.0 (81.6) 106.1 (73.7) 3.79" score (n=32) (n=38) At follow-up Patient total BSS 155.7 (84.2) 132.6 (90.2) 2.41x score (n=18) (n=35) Patient groups were similar in terms of age, weight and gender distributions. There were no significant differences between patients in the two treatment groups on entry in terms of total severity of symptoms as judged independently by both the patient and gastroenterologist, and no significant differences in duration of the disease as self 5 reported by patients. However, patients allocated to the placebo group did register a higher mean score for constipation, whilst patients allocated to the standard treatment group registered a higher mean score for diarrhoea. Compliance with medication was high as measured by a questionnaire item and by random pill counts, and did not differ between groups. Fibre and medication consumption did not alter significantly for any 10 group during the treatment period. (i) Reliability testing The reliability of the BSS (ie the consistency of the measure) was determined by a test-retest assessment during the run-in period prior to treatment commencing (week WO 00/25801 PCT/AU99/00945 - 11 0 to week 2). Patients were invited to complete the BSS during the initial interview with the gastroenterologist and then two weeks later at the clinical treatment centers prior to treatment commencing. Correlation between the first completion of the bowel symptom scale (BSS1) and the second (BSS2) was high for the total score (r=0.7, p<0.01, two 5 tailed) and for each individual symptom (bloating (r=0.8), pain (r=0.6), diarrhoea (r=0.8) and constipation (r=0.7)). The high test-retest reliability between the two scale scores indicates the test is reliable on repeated administration and that the patients' presentation of their condition was relatively stable. The credibility scale was also examined for test-retest reliability. Correlation 10 between the first and second administration of this scale was significant (r=0.6, p<0.01, two-tailed). The correlation coefficients for each of the four scale items fell in the range of 0.47 to 0.65. The internal consistency of the credibility scale was explored by examining inter-item correlations on each of the first two occasions. Inter-item correlations on both occasions were uniformly high and Cronbach's coefficient alpha 15 (representing average inter-item correlations) was 0.87 and 0.86 for the first and second occasions, respectively. (ii) Validity testing The visual analogue scales within the BSS had high face validity (100mm lines with severity marked at the extreme right and absence of symptom marked at the 20 extreme left), and have high content validity (in that they incorporate the key domains of interest - pain and discomfort, bloating, constipation and diarrhoea). The items in the scale were also tested for concurrent validity against the gastroenterologist assessment at the commencement and at the end of the treatment period. At these times both patients and gastroenterologists completed the visual analogue scales independently. 25 The gastroenterologist assessment of the patient correlated highly with the patient's own perception of severity of symptoms. (On both occasions Pearson's correlation coefficient was in the range of r=0.63 to r=0.84 for any one item (symptom) or for the total symptom score) (p<0.01 on all occasions). The credibility scale was assessed for construct validity through a principal 30 components factor analysis based on the first administration. The results revealed only one factor with an eigenvalue greater than 1 (2.89). This factor accounted for 72.2% of variance in this data set. All items had a high correlation with this first factor. This suggests that there was a satisfactory level of construct validity of this scale.

WO 00/25801 PCT/AU99/00945 - 12 (iii) Main outcome measures Five distinct outcome measures are reported here - total mean bowel symptom scales and global improvement as recorded by patients and gastroenterologists, and interference with life as recorded by patients. On all measures, patients receiving the 5 standard herbal formulation of the present invention responded significantly better than patients in the placebo group. (iv) Bowel symptom scales The bowel symptom scales were completed by patients at various stages during the course of treatment including upon completion of the trial. An analysis of variance 10 (ANOVA) test performed at the end of treatment demonstrated a significant difference between the mean total symptom scores for patients in each group, the standard herbal treatment patients responding significantly better compared to placebo (F=3.8; df 2, 96; p<0.05) (Table 5). The bowel symptom scale was also completed by the gastroenterologist on 15 reviewing the patient at the end of the treatment period. Analysis of variance showed a significant difference between the mean total symptom scores for patients in each group, with standard herbal treatment patients responding significantly better compared to placebo (F=7.9; df 2, 87; p<0.05). Patients receiving the standard herbal formulations improved by 44% (according 20 to patients) and 59% (according to gastroenterologists), in contrast to patients in the placebo group who improved 22% (according to patients) and 19% (according to gastroenterologists). (v) Interference with life An item was included in the BSS asking patients to assess the degree of 25 interference with life and activities. Responses allowed for a grade of severity of interference to be recorded. This item was included on each occasion the patient completed the BSS. Change in the severity score for this item was calculated for each patient. A significant association was found between the treatment groups and the 2 change in grade of interference by the end of treatment (p=0.03, df=4, X =10.6). 63% 30 of patients receiving the standard formulation stated treatment resulted in less interference in their lives and activities, in contrast to 37% of placebo patients. (vi) Global improvement At the end of the trial both gastroenterologists and patients were asked whether they felt the IBS symptoms had improved, stayed the same or worsened (Table 6).

WO 00/25801 PCT/AU99/00945 - 13 Table 6: Perception of improvement by treatment group (percentages of respondents in brackets) Compared to Placebo group Standard group before trial Patient Improved 11 (33%) 29 (76%) response Chi-square Stayed the 19 (57%) 8 (21%) p=0.007 same Worsened 3 (9%) 1 (3%) Gastroenterolo Improved 9 (30%) 29 (78%) gist response Chi-square Stayed the 19 (63%) 7 (19%) p=0.002 same Worsened 2 (7%) 1 (3%) A significant association between the treatment group and how patients felt at 2 the end of treatment was observed (p=0.007, df=4, X = 14.3). 76% of patients receiving 5 the standard formulation stated they had improved during treatment. In contrast, only 33% of patients receiving placebo stated they had improved during treatment. The gastroenterologists' responses also demonstrated a significant association between the treatment group and how patients felt at the end of treatment (p=0.002, 2 df=4, X =17.1). 78% of patients receiving the standard formulation were identified as 10 having improved during treatment. In contrast, only 30% of patients receiving placebo perceived having improved during treatment. There was significant correlation between patients' and gastroenterologists' assessment of global improvement and of total BSS scores at the beginning and end of the trial (all r>0.5, all significant to 0.01 level, 2-tailed). 15 (vii) Follow-up assessment The BSS was administered to patients one final time 14 weeks after completion of the course of treatment. Treatment codes were not revealed to patients until after completion of this final follow-up questionnaire, hence patients were still blinded. Blinding of patients was verified. 20 Patients still responded as having made notable improvement when compared to before the trial. A chi-square test performed on the patient responses demonstrated a significant association between the treatment group and how patients felt at the point WO 00/25801 PCT/AU99/00945 - 14 of follow-up (p=0.02, df=4, X 2 =1 1.5). 63% of patients who had received the standard formulation stated they still felt improved. Notably, 32% of patients who had received placebo stated they still felt improved. Herbalism, acupuncture, homeopathy and manual therapies (eg osteopathy) 5 frequently rely on a second diagnostic process distinct from western medicine and an high degree of interaction between the patient and practitioner during the treatment. The former leads to a clinical distinction between what seem to be similar diagnostic cases in western medicine (individualisation of therapy). The latter demands that the therapeutic intervention be continuously modified in response to patient feedback. 10 Treatment needs to be tailored to the individual at the outset and also modified at differing stages of the patient's illness. Rigorous clinical trial methodology frequently imposes standardisation of treatment for trial subjects. The present study has demonstrated that Chinese herbal medicine is effective in the management of irritable bowel syndrome with, in some cases, effects lasting up 15 to 14 weeks after completion of treatment. At the outset of the study there were no significant differences between patients in each group. They were well matched for age, gender, weight, severity and duration of illness. Patients receiving standard herbal treatment demonstrated significantly better outcomes (both clinically and statistically) than patients receiving the placebo treatment on all five key outcome measures. 20 A conclusion can be drawn that Chinese herbal formulations of the present invention may offer substantial assistance to patients with irritable bowel syndrome and constitute an alternative treatment option for the management of IBS. A person skilled in the art will understand that the therapeutic effects of the compositions result from a plurality of active agents in each herb which when combined, 25 act synergistically to enhance efficacy. It will also be understood that compositions comprising all or a selection of such active agents, preferably in pure form, are also contemplated herein, as are liquid formulations of the composition and formulations which are suitable for slow release administration. Thus it will be understood that the compositions of the invention can be administered orally, intravenously, topically or by 30 other known means. The invention may be embodied in various other forms which are understood by those skilled in the art.

WO 00/25801 PCT/AU99/00945 - 15 REFERENCES 1. Drossman DA, Li Z, Andruzzi E, Temple R, Talley NJ, Thompson WG, et al. U.S. householder survey of functional gastrointestinal disorders: prevalence, sociodemography and health impact. Dig Dis Sci. 1993;38:1569-1580. 5 2. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ Ill. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology. 1991;101:927-934. 3. Heaton KW, O'Donnell LJD, Braddon FEM, Mountford RA, Hughes AO, Cripps PJ. Irritable bowel syndrome in a British urban community: consulters and non-consulters. Gastroenterology. 1992;102:1962-1967. 10 4. Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ. 1992;304:87-90. 5. Talley NJ, Boyce PM, Owen BK, Newman P, Paterson KJ. Initial validation of a bowel symptom questionnaire and measurement of chronic gastrointestinal symptoms in Australians. Aust NZ J Med. 1995;25:302-307. 15 6. Talley NJ, Owen BK, Boyce P, Paterson K. Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials. Am J Gastroenterology. 1996;91:277-283. 7. Klein KB. Controlled treatment trials in the irritable bowel syndrome: a critique. Gastroenterology. 1988;95:232-241. 20 8. Bensoussan A, Myers SP. Towards a Safer Choice: the practice of Traditional Chinese Medicine in Australia. Sydney: University of Western Sydney Macarthur, 1996. 9. Yu ZX, Wang K & Li FP. Clinical trial of Chinese herbal capsule for 157 cases of irritable bowel syndrome. China Journal of Integrated Chinese and Western Medicine. 1991;11:170-171. 25 10. Liu ZK. Chinese herbal medicine treatment for 120 cases of irritable bowel syndrome. China Journal of Integrated Chinese and Western Medicine. 1990; 10:615. 11. Shi ZQ. Combination treatment of Chinese and Western medicine for 30 cases of irritable bowel syndrome. China Journal of Integrated Chinese and Western Medicine. 1989;9:241. 30 12. Chen DZ. Tong Xie Yao Fang with additions in treating 106 cases of irritable bowel syndrome. Nanjing Medical University Journal. 1995;15:924. 13. Xu RL. Clinical realisations during the diagnosis and treatment of 55 cases of irritable bowel syndrome. Shanxi Journal of Traditional Chinese Medicine. 1995;11:10 11.

WO 00/25801 PCT/AU99/00945 - 16 14. Anthony HM. Some methodological problems in the assessment of complementary therapy. In: Lewith GT, Aldridge D, eds. Clinical Research Methodology for Complementary Therapies. London: Hodder & Stoughton; 1993:108-121. 15. Bensoussan A. Contemporary acupuncture research: the difficulties of research 5 across scientific paradigms. Amer J Acup. 1993;19:357-366. 16. Thompson WG, Creed F, Drossman DA, Heaton KW, Mazzacca G. Functional bowel disease and functional abdominal pain. Gastroenterology International. 1992;5:75-91. 17. Talley NJ, Nyren 0, Drossman DA, Heaton KW, Veldhuyzen van Zanten SJO, Koch 10 MM, et al. The irritable bowel syndrome: toward optimal design of controlled treatment trials. Gastroenterology International. 1993;6:189-211. 18. Borkovec TD, Nau SD. Credibility of analogue therapy rationales. J Behav Ther Exp Psychiat. 1972;3:257-260. 19. Vincent C. Credibility assessment of trials in acupuncture. Complementary Medical 15 Research. 1990;4:8-11. 20. Petrie J, Hazleman B. Credibility of placebo transcutaneous nerve stimulation and acupuncture. Clin Exp Rheumatol. 1985;3:151-153. 21. Kane JA, Kane SP, Jain S. Hepatitis induced by traditional Chinese herbs: possible toxic components. Gut 1995;36:146-147. 20

Claims (16)

1. Composition including the herbs Ledebouriellae Sesloidis, Bupleurum Chinense, Artemesiae Capillaris, Fraxini, Plantaginis, Paeoniae Lactiflorae and Schizandrae. 5

2. Composition including at least two herbs selected from the group consisting of Codonopsis Pilosulae, Atractylodis Macrocephalae, Poriae Cocos and Glycyrrhizae Uralensis, any two herbs selected from the group consisting of Agastaches seu Pogostemi, Magnoliae Officinalis, Citri Reticulatae and Saussureae seu Vladimiriae, any two herbs selected from the group consisting of Phellodendri, Coptidis, Coicis 10 Lachryma-jobi, Zingiberis Offinicinalis and Angelicae Dehuricae, and any two herbs selected from the group consisting for Ledebouriellae Sesloidis, Bupleurum Chinense, Artemesiae Capillaris, Fraxini, Plantaginis, Paeoniae Lactiflorae and Schizandrae.

3. Composition including the herbs Codonopsis Pilosulae, Agastaches seu Pogostemi, Ledebouriellae Sesloidis, Coicis Lachryma-jobi, Bupleurum Chinense, 15 Artemesiae Capillaris, Atractylodis Macrocephalae, Magnoliae Officinalis, Citri Reticulatae, Zingiberis Offinicinalis, Fraxini, Poriae Cocos, Angelicae Dehuricae, Plantaginis, Phellodendri, Glycyrrhizae Uralensis, Paeoniae Lactiflorae, Saussureae seu Vladimiriae, Coptidis and Schizandrae.

4. A composition according to any one of claims I to 3, which is formulated with 20 powdered herbs.

5. A composition according to any one of claims 1 to 3, which includes extracts of the herbs.

6. A composition according to any one of claims I to 3, in a capsule or tablet dosage form. WO 00/25801 PCT/AU99/009-45 - 18

7. A composition according to any one of claims 1 to 3, further including pharmaceutically acceptable excipients, adjuvants, solvents, carriers, flavours, colourings or coatings. 5

8. Method of treating gastrointestinal disorders including the administration to a subject requiring such treatment a composition according to any one of claims 1 to 7.

9. A method according to claim 8, wherein the gastrointestinal disorder to be treated is Irritable Bowel Syndrome (IBS).

10. A method according to claim 8 or claim 9, wherein the treatment is administered 10 orally.

11. A method according to any one of claims 8 to 10, wherein the treatment is therapeutic or prophylactic and may be administered in a single bolus dose, multiple doses or via a slow release device.

12. Composition according to any one of claims I to 7 for use as a medicament. 15

13. Use of a composition according to any one of claims 1 to 7 for the manufacture of a medicament for treatment of gastrointestinal disorders.

14. Use according to claim 13, wherein the gastrointestinal disorder is Irritable Bowel Syndrome (IBS).

15. Use according to claim 13 or claim 14, wherein the medicament is formulated for 20 oral administration.

16. Use according to any one of claims 13 to 15, wherein the medicament is WO 00/25801 PCT/AU99/00945 - 19 formulated for administration in a single bolus dose, multiple dose or via a slow release device.