DISORDER

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 62/871,335, filed July 8, 2019, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention provides a composition and method for treating gastrointestinal disorder.

BACKGROUND OF THE INVENTION

[0003] Constipation and/or diarrhea, while not life-threating, have caused much comfort affecting the quality of life. Recently, functional bowel disorder (FBD) has been defined as a disorder w ith symptoms attributable to the mid or lower gastrointestinal tract, including functional constipation, functional diarrhea and irritable bowel syndrome (IBS), although the precise etiologic basis of FBD is not known. FBD is diagnosed by characteristic symptoms in the absence of a structural or biochemical explanation; and with respect to IBS, the most common symptoms are abdominal pain or discomfort associated with alternating constipation and diarrhea. It is assumed that IBS is a complex disorder with physiologic and psychosocial components in which altered motility or sensation in the intestine is modulated by input from the central nervous system. The treatments most commonly recommended for FBD are dietary fiber/bulking agents

[0004] Constipation is a disorder in the gastrointestinal tract, with the clinical manifestations of infrequent stools, difficult stool passage with pain and stiffness. The lack of ideal definition of constipation has led to a wide range of reported prevalence (i.e., between 1% and 80%, worldwide). Furthermore, chronic constipation is a complicated condition among older individuals. In this regard, this condition has a close relationship

with the patients’ quality’ of life, and consuming health resources. [0005] The muitifactorial causes of constipation limit the clinical efficacy of current conventional treatments that use a single drug that acts through only one pathway. However, herbal medicines are emerging remedies for constipation because of their capability to target multiple pathways.

[0006] Cinnamomum is a genus in the Laurel family, Lauraceae, little of which are studied for their laxative activity from leaves.

BRIEF SUMMARY OF THE INVENTION

[0007] It is unexpectedly found in the present invention that leafs of stout camphor tree or extract thereof are effective in amelioration or inhibition of a gastrointestinal disorder, especially a constipation.

[0008] In one aspect, the invention also provides a method for treating a gastrointestinal disorder, especially a constipation, which comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of leafs of stout camphor tree or extract thereof, optionally in association with a pharmaceutically acceptable carrier.

[0009] In another aspect, the invention also provides a composition/pharmaceutical composition for treating a gastrointestinal disorder, especially a constipation, which comprises a therapeutically effective amount of leafs of stout camphor tree or extract thereof, and a pharmaceutically acceptable carrier.

[0010] In a further aspect, the invention provides a use of leafs of stout camphor tree or extract thereof for preparing a medicament for a gastrointestinal disorder, especially a constipation.

[0011] According to the invention, it was ascertained in the examples that leafs of stout camphor tree or extract thereof have laxative activity.

[0012] In one embodiment of the present invention, the gastrointestinal disorder is selected from the group consisting of constipation, reflux oesophagitis, autism enteropathy, flatulence, halitosis, Chronic Fatigue Syndrome (CFS), bloating, proctalgia fugax, small intestinal bacterial overgrowth (SIBO) and large intestinal bacterial overgrowth (LIBO), chronic nausea, functional dyspepsia, and bloating.

[0013] In one particular embodiment of the present invention, the gastrointestinal disorder is constipation. [0014] In one embodiment of the invention, the extract of leafs of stout camphor tree is a water extract or an ethanol extract.

[0015] In one embodiment of the invention, the leafs of stout camphor tree and extract thereof are substantially safrole free.

[0016] In one embodiment, the composition/pharmaceutical composition further comprises at least one additional laxative.

[0017] In one embodiment, the composition/pharmaceutical composition further comprises at least one additional probiotic.

[0018] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0019] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred.

[0020] In the drawings :

[0021] Figure I is an illustrative gas chromatographic-mass spectrometric (GC-MS) chromatogram of the water extract of the leafs of stout camphor tree (LESCT-A).

[0022] Figure 2 is an illustrative GC-MS chromatogram of the ethanol extract of the leafs of stout camphor tree (LESCT-B).

[0023] Figure 3 shows effects of LESCT-A and LESCT-B on intestinal charcoal transit. Loperamide administration significantly reduced intestinal charcoal transit in the untreated constipated mice.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The above summary of the present invention will be further described with reference to the embodiments of the following examples. However, it should not be understood that the content of the present invention is only limited to the following embodiments, and all the inventions based on the above-mentioned contents of the present invention belong to the scope of the present invention.

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention belongs.

[0026] As used herein, the singular forms“a”,“an”, and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“a sample” includes a plurality of such samples and equivalents thereof known to those skilled in the art.

[0027] The present invention provides a a method for treating a gastrointestinal disorder, especially a constipation, which comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of leafs of stout camphor tree or extract thereof, optionally in association with a pharmaceutically acceptable carrier.

[0028] The present invention also provides a composition/pharmaceutical composition for treating a gastrointestinal disorder, especially a constipation, which comprises a therapeutically effective amount of leafs of stout camphor tree or extract thereof, and a pharmaceutically acceptable carrier.

[0029] Furthermore, the present provides a use of leafs of stout camphor tree or extract thereof for preparing a medicament for a gastrointestinal disorder, especially a constipation.

[0030] In one embodiment of the invention, the composition/pharmaceutical composition of claim 1 may be prepared in form of a drink. In one particular embodiment of the invention, the leafs of stout camphor tree may be prepared in the form of a tea bag.

[0031] The term“gastrointestinal disorder’ as used herein refers to any condition which can benefit from speeding bowel transit, including, constipation, reflux oesophagitis, autism enteropathy, flatulence, halitosis, Chronic Fatigue Syndrome (CFS), bloating, proctalgia fugax, small intestinal bacterial overgrowth (SIBO) and large intestinal bacterial overgrowth (LIBO), chronic nausea, functional dyspepsia, and bloating.

[0032] The term“constipation” as used herein refers to a constipation, functional constipation, a chronic constipation, an acute constipation, Irritable Bowel Syndrome (IBS)- constipation, diverticulosis-associated constipation, pseudo obstruction, slow-transit constipation, stasis with overflow and diabetic gastro-paresis. [0033] The term“other disorders with related gastrointestinal symptoms’ as used herein refers to any condition which can benefit from speeding bowel transit, including reflux oesophagitis, autism enteropathy, flatulence, halitosis, Chronic Fatigue Syndrome (CFS), bloating, proctalgia fugax, small intestinal bacterial overgrowth (SIBO) and large intestinal bacterial overgrowth (LIBO), chronic nausea, functional dyspepsia, and bloating.

[0034] The term“treating” as used herein refers to the application or administration of a composition including one or more active agents to a subject afflicted w ith a disease, a symptom or conditions of the disease, or a progression of the disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease, the symptoms or conditions of the disease, the disabilities induced by the disease, or the progression of the disease.

[0035] The term“subject” as used herein includes human or non-human animals, such as companion animals (e.g. dogs, cats, etc.), farm animals (e.g. cattle, sheep, pigs, horses, etc.), or experimental animals (e.g. rats, mice, guinea pigs, etc.).

[0036] The term“therapeutically effective amount” as used herein refers to an amount of a pharmaceutical agent which, as compared to a corresponding subject who has not received such amount, results in an effect in treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0037] For use in therapy, the therapeutically effective amount of the compound is formulated as a pharmaceutical composition for administration. Accordingly, the invention further provides a pharmaceutical composition comprising a therapeutically effective amount of leafs of stout camphor tree or extract thereof, and one or more pharmaceutically acceptable carriers.

[0038] For the purpose of delivery and absorption, a therapeutically effective amount of the leafs of stout camphor tree or extract thereof according to the present invention may be formulated into a pharmaceutical composition in a suitable form with a pharmaceutically acceptable carrier. Based on the routes of administration, the leafs of stout camphor tree or extract thereof are in the amount of 0.1 % to 100% in weight of the total weight of the composition. [0039] The term "pharmaceutically acceptable carrier" used herein refers to a carrier(s), diluent(s) or excipient(s) that is acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject to be administered with the pharmaceutical composition. Any carrier, diluent or excipient commonly known or used in the field may be used in the invention, depending to the requirements of the pharmaceutical formulation.

According to the invention, the pharmaceutical composition may be adapted for

administration by any appropriate route, including but not limited to oral, rectal, nasal, topical, vaginal, or parenteral route. In one particular example of the invention, the pharmaceutical composition is formulated for oral administration. Such formulations may be prepared by any method known in the art of pharmacy.

[0040] As used herein,“pharmaceutically acceptable” means that the carrier is compatible with the active ingredient in the composition, and preferably can stabilize said active ingredient and is safe to the individual receiving the treatment. Said carrier may be a diluent, vehicle, excipient, or matrix to the active ingredient. Some examples of appropriate excipients include lactose, dextrose, sucrose, sorbose, mannose, starch, Arabic gum, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterilized water, syrup, and methyicellulose. The composition may additionally comprise lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoales; sweeteners; and flavoring agents. The composition of the present invention can provide the effect of rapid, continued, or delayed release of the active ingredient after administration to the patient.

[0041] According to the present invention, the form of said composition may be diink, tea bag, tablets, pills, powder, suspensions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterilized injection fluid, and packaged powder.

[0042] The composition of the present invention may be delivered via any

physiologically acceptable route, such as oral, parenteral (such as intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods.

Preparation of an appropriate parenteral composition under sterile conditions may be accomplished with standard pharmacological techniques well known to persons skilled in the art.

[0043] According to the present invention, the method and composition/pharmaceutical composition described herein could be administrated a subject in combination with at least one additional laxative. Exemplified laxatives which are responsive include, without limitation a bisacodyl (e.g., a DULCOLAX™, a DUROLAX™, a FLEET™ an

ALOPHEN™, or a CORRECTOL™), a docusate sodium, a poloxamer, a sennoside, a lactulose, a sorbitol, a sugar, a sterculia or frangula, a paraffin oil or an equivalent thereof or a combination thereof. Another example of the additional laxative is probiotics, which may be a cultured or stool-extracted microorganism or bacteria, or a bacterial component, and optionally the bacteria or bacterial component comprises or is derived from a Bacteroidetes, a Firmicutes, a Lactobacilli, a Bifidobacterium, an E coli, & Strep faecaiis and equivalents.

[0044] The present invention is further illustrated by the following examples, which are provided for the purpose of demonstration rather than limitation.

[0045] Examples

[0046] Materials and Methods

[0047] 1. Preparation of leaf extracts of stout camphor tree

[0048] Leaf extracts of stout camphor tree (LESCT) were obtained from the ARJIL pharmaceuticals LLC. For preparing LESCT, the fresh leaves of stout camphor tree were applied to indoor withering/tossing, streaming, and rolling. The processed leaves were allowed to hot air drying at 50-150 °C, and then subjected to ethanolic and water extraction to obtain LESCT-A and LESCT-B fractions, respectively.

[0049] 2. Analysis of safrole in LESCT

[0050] 15 g of the leave of stout camphor tree was extracted using 200 mL of water or

200 mL of 95% ethanol by heating circumfluence. The extracts were then subjected water/dichloromethane partition and the dichloromethane partitions w ere analyzed by a gas chromatographic-mass spectrometric (GC-MS) system to detect the presence of safrole.

[0051] 3. Experimental animals

[0052] Male ICR mice (7-8 weeks) were obtained from the BioLASCO Taiwan Co.,

Ltd. (Taipei, Taiw an). The animals were housed in Plexiglas cages at a constant temperature of 22 ± 1 °C and a relative humidity of 55 ± 5% on a 12 h dark-light cycle for at least 2 weeks before the experiment. Animals were provided food and water ad libitum. All experimental procedures were performed according to the guidelines of the Institutional Animal Ethics Committee, and the protocol was approved by the Committee for the Purpose of Control and Supervision of Experiments on Animals.

[0053] 4. Induction of constipation in the mice

[0054] Constipation was induced in the animals by oral administration of 1 mL loperamide (10 mg/kg body weight in 0.9% sodium chloride), while the control mice were administered with the normal saline only. The passage of reduced, hard and diy fecal pellets indicated constipation in the mice.

[0055] 5. Experimental design

[0056] The mice were grouped into six of five mice each. The animals in Group 1 (control) and Group 2 (constipated control) were administered with distilled water. Groups 3, 4 5 and 6 comprised constipated mice given LESCT-A (0.25, 0.5, and 1 g/kg) and LESCT-B (0.5 g/kg) body weight/ day, respectively. The water intake, feed intake and body weight gain of all the mice were recorded during experimental period and treatment continued for 7 days. 7 days after the test samples were given, each group of mice was fasted for 16 hours. After 1 hours, loperamide (10 mg/kg) was intragastrically administered to the model control group (Group 2) and experimental groups (Group 3, 4, 5 and 6), and the blank control group (Group 1) was given distilled water.

[0057] 6. Total number, time and dry weight of fecal pellet

[0058] Total number, time and weight of the pellets were determined. The defecation time of the first time in the mice, the number of defecations and the weight of the defecation in 6 horns were measured to reflect the defecation of the model mice.

[0059] 7. Measurement of intestinal charcoal transit ratio

[0060] Seven days after the test samples were given, but consumed water ad libitum. 0.5 horn s after the administration of loperamide-induced constipation, the animals were fed charcoal meal (1 mg/ 100 kg weight) (5% suspension of activated charcoal in 10% gum arabic). At 30 min after the charcoal meal administration, the animals w'ere first sacrificed by cervical dislocation and the abdominal cavity was then opened. The intestines were removed and the total intestine length (from pyloric sphincter to cecum) and charcoal meal transit distance were measured. The intestinal charcoal transit ratio was calculated as follows: charcoal transit ratio (%) = (distance travelled by the charcoal) / (total length of small intestine) * 100%.

[0061] 8. Statistical analysis

[0062] Data obtained from animal experiments were expressed as the means and standard errors of the means (± S.E.M.). Student's t-test were used to examine the differences among multiple groups or between two groups. Statistical significance is expressed as * p < 0.05, ** p < 0.01 and *** p < 0.001.

[0063] Example 1

[0064] Analysis of the presence of safrole in LESCT

[0065] Safrole is a phenylpropenoid found in a wide variety of plants, where it functions as a natural antifeedant. However, toxicological studies have revealed that

metabolic conversion of safrole contributes to carcinogenicity. To determine the presence of safrole in LESCT, LESCT-A and LESCT-B were subjected to GC-MS analysis, and the results showed that safrole cannot be detected in both LESCT-A (Figure 1) and LESCT-B (Figure 2). Furthermore, camphor was also absent in both LESCT-A (Figure 1) and LESCT- B (Figure 2). These data together indicate that safrole and camphor were removed during the process of extraction in the present invention.

[0066] Example 2

[0067] Effects of LESCT on intestinal charcoal transit

[0068] In the loperamide-treated group, a loss of intestinal charcoal transit is recorded after administration of loperamide and this loss remained significantly (p < 0.001) higher compared with the group of normal mice until day 7 (from 57.63 ± 3.32 cm to 27.94 ± 3.86 cm). A statistically significant decrease in the intestinal charcoal transit ratio was detected in the loperamide + LESCT-A (0.25, 0.5, and 1 g/kg) (p < 0.001) and LESCT-B (0.5 g/kg) (p < 0.01) when compared with the loperamide group. Loperamide administration significantly reduced gastrointestinal motility in the untreated constipated mice. The treatment with the extract (LESCT-A and LESCT-B), however, increased the gastrointestinal movement in a dose dependent manner which compared with loperamide-induced constipation in mice.

[0069] Example 3 [0070] Loperamide-induced constipation on time and fecal properties of constipated mice was inhibited by LESCT

[0071] Constipation was assessed principally by time, fecal pellet number and weight to determine the effects of the water extract of the leafs of stout camphor tree (LESCT-A) and the ethanol extract of the leafs of stout camphor tree (LESCT-B) on loperamide-induced constipation. Loperamide significantly reduced time, the number and the weight of the fecal pellets (Table 1), indicating the induction of constipation in the mice. It was found that the extracts, LESCT-A and LESCT-B significantly decreased the time of loperamide-induced constipation and increased the number and weight of fecal pellets in the constipated mice.

Table 1. Effects of LESCT-A and LESCT-B in the loperamide-induced constipation on time and fecal properties of constipated mice

** *p < 0.001, were compared with the loperamide-induced constipation group. [0072] It was demonstrated that LESCT-A and LESCT-B had laxative activity. The oral administration of LESCT-A and LESCT-B provided a laxative effect in loperamide induced constipated mice, suggesting that the beneficial effects of the extracts provide effects in improving intestinal motility. It was also found that LESCT-A at 0.5 g/kg body weight provided a better effect than LESCT-B. at 0.5 g/kg body weight. In conclusion, the extracts are potential to develop a therapeutic agent for treatment of constipation.

[0073] The above description merely relates to preferred embodiments in the present invention, and it should be pointed out that for a person of ordinary skill in the art, some improvements and modifications can also be made under the premise of not departing from the principle of the present invention, and these improvements and modifications should also be considered to be within the scope of protection of the present invention.