Patent Application
20140116916
The present invention relates to methods and compositions for the treatment of bowel disorders, especially constipation associated with the administration of painkillers.
Constipation is a frequent side effect of many conditions and medications. For example, opioids may lead to constipation since these agents decrease peristaltic activity in the gastrointestinal (GI) tract. Because of the mechanisms involved in opioid-induced constipation, some treatments that may be applicable for common, functional constipation are inappropriate for ambulatory-care patients prescribed opioid analgesics. Also in these patients, the distress of constipation may add to the discomfort already present from pain, and they might decrease or discontinue the opioid to avoid constipation. Therefore motivating such patients to comply with their opioid therapy also requires an approach for managing constipation
Constipation is broadly defined as the passage of hard, dry stools less frequently than the patient's usual bowel-habit pattern.
Constipation resulting from opioid use is the most common component of a more general condition called opioid-induced bowel dysfunction, OBD. Signs and symptoms of OBD include dry hard stools, straining during evacuation, incomplete evacuation, bloating, abdominal distension, and retention of the contents of the bowel.
Bulk-forming laxatives are typically not appropriate in opioid-induced constipation because peristalsis is inhibited in these patients so stool softener and bowel stimulants are often used. Some patients may take mild over-the-counter bulk laxatives and fail to mention this to their physician. This can result in painful, colic-like symptoms.
Attempts have been made to solve the problem of opioid induced constipation. For example, U.S. Pat. No. 6,982,283 discloses a method for treating drug-induced constipation that comprises administering an effective amount of 15-keto-prostaglaindin compound to a subject suffering from drug-induced constipation or a subject having a strong possibility of suffering from it. U.S. Pat. No. 8,278,323 describes certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use as opioid receptor antagonists for the treatment of opioid induced constipation. The use of an opioid antagonist effectively reduces the amount of physiologically available opioid. However, the dose that leads to constipation is approximately four-fold less than the dose required for an analgesic response.
In one aspect of the invention, there is provided a method of treating acute, sub-acute or chronic constipation in a patient having a condition requiring such treatment, comprising the administration of a lipase inhibitor.
In one preferred embodiment the lipase inhibitor is selected from the group consisting of: orlistat, atl-962 (cetalstat) and gt389-255.
In another preferred embodiment, the lipase is naturally and comprise saponins, platycodin saponins, scabio saponins, sessiloside and chiisanoside, chikusetsusaponins, dioscin and derivatives, escins, teasaponins, cyclocariosides, polyphenoics, oolong tea polyphenols, polyphenol rich extracts including grape seed extract, nelumbo nucifera extract, salacia reticulata hot water extract, peanut shell extract, mangifera indica leaf and steam bark extracts, ct-ii extracts, terpenes including carnosic acid, crocin and crocetin and pancreatic lipase inhibitors from microbial sources such as lipstatin.
In another embodiment the condition is selected from the group consisting of opiod administration, dehydration, lazy bowel, paralytic bowel, menstruation related constipation, bowel resection and being bedridden.
In a further embodiment the lipase inhibtor is administered topically, IM, IV, SC, or mucosally.
In yet another embodiment the preferred lipase inhibitor is orlistat or cetalstat
In another aspect the invention is a method for treating chronic pain comprising administering a pain medication in combination with a lipase inhibitor.
In another aspect of the invention there is provided a composition for the treatment of chronic constipation comprising 30 to 150 mg of a lipase inhibitor.
In a preferred embodiment the composition is formulated for oral administration.
In another embodiment the composition is in the form of a tablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet or other combining vehicle, elixir, powder, including lyophilised powder, solution, granule, suspension, emulsion, syrup or tincture. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.
In another embodiment the composition is provided in a compliance-enhancing blister pack
The present invention provides a novel method of treatment for constipation. This novel type of treatment has a much improved therapeutic result for those who are suffering chronic constipation related to the use of opiates, other pain-killers, antidepressants and other situations such as paralysis, infection, cancer, radiation therapy and dehydration.
Lipase inhibitors are typically used for aiding weight loss. The active ingredient in some of the prescription products such as Xenical and Alli is orlistat. Other lipase inhibitors that function in the same way are herbal or are naturally sourced.
Lipase inhibitors block the action of the two compounds found in the digestive juices of the stomach and small intestine. These enzymes are known to break down the fat molecules that are in our diet. Without the action of these compounds, the molecules of fat are too large to be digested by our stomach and then to enter our bloodstream. Lipase inhibitors essentially keep the fat molecule intact and undigested thus instead of becoming part of the body, the fat is excreted as waste through the bowels.
One of the known side effects of lipase inhibitors like Xenical is that the patient may experience loose bowels including episodes of diarrhea. This is of course a negative side effect for those persons who are taking the medication for weight-loss.
For those persons facing a problem of chronic constipation, the use of lipase inhibitors offers a new treatment alternative. The lipase inhibitors that block the production of pancreatic and gastric enzymes that break down fat provided to treat chronic constipation is a novel use for these compounds.
The present invention provides a novel approach to the provision of such antigens and immunogens by inactivation of purified RS virus.
According to the present invention synthetic, chemical or naturally derived lipase inhibitors can be used to relieve chronic constipation for persons who are using opiates, painkillers or other constipating treatments.
Some examples of lipase Inhibitors that may be used in the method of the present invention include orlistat which is a pancreatic lipase, atl-962 (also known as cetilistat) which is another pancreatic lipase and gt389-255 which is another lipase inhibitor
In addition, according to the invention naturally sourced lipase inhibitors may be used. These include plants such as, but are not limited to, saponins, platycodin saponins, scabio saponins, sessiloside, chiisanoside, chikusetsusaponins, dioscin and derivatives, escins, teasaponins and cyclocarios. The use of polyphenoics such as oolong tea polyphenols are included within the scope of the invention. Also included are polyphenol rich extracts such as grape seed extract, nelumbo nucifera extract, salacia reticulata hot water extract, peanut shell extract, mangifera indica leaf and steam bark extracts ct-II extracts.
Furthermore, terpenes such as carnosic acid, crocin and crocetin may also be used in the present invention. Pancreatic lipase inhibitors from microbial sources such as lipstatin.
In the present invention, various mode of administration may be used. Depending on the formulation, the lipase inhibitor may be administered topically, IM, IV, IM, and via mucosal route.
Compositions of the invention may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenizing, suspending, dissolving, emulsifying, dispersing and, where appropriate, mixing of the colchicine and amino-salicylic acid derivative(s), optionally together with one or more selected excipients, diluents, carriers and adjuvants.
The pharmaceutical composition of the invention may be in the form of a tablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet or other combining vehicle, elixir, powder, including lyophilised powder, solution, granule, suspension, emulsion, syrup or tincture. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules. The composition may also be presented in a compliance-enhancing blister pack.
The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for the purpose of limitation.
Methods of determining tissue culture infectious dose50 (TCID50/mL), plaque and neutralization titres, not explicitly described in this disclosure are amply reported in the scientific literature and well within the scope of those skilled in the art. Protein concentrations were determined by the bicinchoninic acid (BCA) method as described in the Pierce Manual (23220, 23225; Pierce Chemical Company, U.S.A.), incorporated herein by reference.
A 35-year-old female with fibromyalgia presented with chronic pain which is global pain disorder affecting much of her body. She was prescribed opiate medication in the form of MS Contin (60 mg twice a day—BID) for pain management. Since beginning the MS Contin, she suffered from severe constipation. She would often go 7 to 10 days without a bowel movement. She would suffer abdominal discomfort, bloating, and sometimes require manual disempaction due to the severity of her constipation. The patient was given Colace, Sennekot, and bowel stimulants to attempt to correct her chronic constipation related to the pain medication. It was only partially and intermittently successful. She was then given the recommended doses of orlistat (120 mg twice per day orally—BID) with food, and noticed an improvement within 24 hours. Within one week, she had noticed that she had daily bowel movements. She took this new medication for one year and had good well-formed bowel movements most days. She reported no major side effects. This new treatment was seen as a complete success by both the patient and her doctor. She continues the opiate pain management and the orlistat with continued success. This illustrates that the lipase inhibitor improves opiate-related constipation.
A 57-year-old female with fibromyalgia being treated with the tricyclic antidepressant amitriptylline suffers from a global pain disorder requiring pain management. She was treated with amitriptyline that is a known therapeutic agent for mild to moderate fibromyalgia. This tricyclic antidepressant is also known for causing dry mouth, blurry vision and constipation. She had tried Colace and Sennekot (senna) with minimal benefit. The patient was given the recommended dosage of cetilistat (60 mg orally once per day with food) for her chronic constipation and within 24 hours, she had had a bowel movement. She continued the cetilistat daily at one pill per day and was able to acquire regular bowel movements daily. She continued the medication for a year and continues to have good success with daily bowel movements. She reported no major side effects. The cetilistat demonstrated the ability to perform as a long-term therapy for constipation, but also for non-opiate medication related constipation.
A 75-year-old man living in a nursing home with mild dementia complained of painful bowel movements causing an anal fissure with bleeding in his rectum. The cause of his constipation was deemed to be due to a combination of non-opiate medications, dehydration, and a lazy bowel. The patient also complained of abdominal distention and some intermittent abdominal discomfort. A number of common prescription laxatives including Colace, senna, and bowel stimulants caused diarrhea. He had abdominal pain with conventional bowel stimulants. He was then given cetilistat (60 mg orally twice daily with food) which resulted in a bowel movement within 24 to 36 hours that was painless and soft. Over the course of two weeks, the anal fissure had healed and the bleeding had stopped. The patient had regular bowel movements daily and his abdominal bloating and abdominal pain had resolved. The cetilistat resolved the constipation in an acute case and allowed for long-term recovery from a constipation-related complication. Further, it was effective in the treatment of lazy bowel and age-related constipation.
A 25-year-old male travelled to Mexico and while there developed acute gastroenteritis. He began experiencing vomiting and diarrhea while there. He became dehydrated and eventually was transferred to his home in Canada. The virus had cleared one day after arriving back in Canada. He began eating and drinking but had developed constipation related to post-infection and dehydration. He was given orlistat (120 mg orally once daily with food) by his doctor for one week and this resolved his constipation within 24 hours. Furthermore, the orlistat regulated his bowel movements where they became normal and regular. The improvement was such that after seven days that when he stopped the medication (orlistat), he was able to return to his normal diet. His bowel movements continue to be normal after cessation of the orlistat. The orlistat functioned as a short-term solution for severe constipation related to dehydration, post-gastroenteritis, and gastrointestinal illness.
A 45-year-old male suffered a thoracic spinal injury with transection of the spinal cord resulting in complete paralysis below the third thoracic vertebrae. He went on to develop full paralysis of his muscles below T-3 including the skeletal muscles and smooth muscles of the gut. He developed a paralytic bowel contributing to chronic constipation with overflow and diarrhea. He required regular manual disempaction and Fleet enemas to manage his chronic constipation. The patient was given orlistat (120 mg one pill three times a day with food) by his doctor. This allowed for long-term improvement in bowel formation that was soft and allowed for better function of the bowel movements, bowel peristalsis and more regular passage of stool without interventional care such that it reduced the use of enemas and manual disempaction or enemas. The bowel movements were soft and allowing for more regular, daily movements. This allowed for a significant reduction of therapeutic enemas and manual disempaction. This demonstrates effective use of orlistat for paralytic bowel, but also in constipation requiring interventional methods for care.
This is a case of a 35-year-old female who complained of recurring constipation related to her menstrual cycle. She notices that a few days before the onset of her menstrual cycle and for the week of her menstrual cycle she develops constipation that aggravates her bloating and abdominal pain. She has tried over-the-counter laxatives and tried some standard prescription laxatives that caused her to feel more bloated. It did not resolve her constipation. Her doctor gave her a prescription of cetilistat (one 60 mg oral pill once a day with food) to be taken one to three days before the onset of her menstruation. In the fourth week of her period, she noticed normalization of her bowel movement and required to take the cetilistat only as needed. Often she only needs to take it three times during her menstrual cycle. During the days where she used the cetilistat, she had good relief of her constipation with regular, soft bowel movements. She found that the cetilistat was effective in her constipation, but also found she only required the cetilistat on a as needed basis, and her bowel movements were normal during the other days of her cycle. Typically, she required the cetilistat 3-7 days per cycle. This demonstrates effectiveness of cetilistat for the treatment of constipation related to dysmennorhea, but may also apply to disease or illness-related constipation. Further, the cetilistat may be used as needed as a medication for constipation.
A 55-year-old male suffering from bowel cancer was given a partial bowel resection with a colostomy and bag. He complained that since his bowel surgery he suffered chronic constipation and hard stools. When he tried the stool softeners, there was some improvement but he still suffered bloating, constipation and abdominal pain. It would sometimes be so hard it could injure and cause bleeding to the ostomy site. His doctor gave him a prescription for orlistat (120 mg orally once daily with food) and this regulated his bowel movements to an average of once a day, softened his stool which allowed for easy passage of his stool through the ostomy site. His problem with bloating greatly improved and he no longer had abdominal pain. This demonstrates the benefits of orlistat for constipation in those who have had colostomies, bowel resection and bowel cancer or neoplasms.
A 35-year-old male suffered a head injury in a car accident causing a coma that resulted in the individual being bedridden for three months. During that time, due to lack of movement and deconditioning (being bed-ridden), the patient developed severe constipation requiring Fleet enema and disempaction. He was given a number of prescription laxatives including Colace, senna and bowel stimulants with some improvement but still required regular lower bowel lavage with Fleet enema and manual disempaction. He was given orlistat (initially one 120 mg pill once a day orally with food and then was gradually increased to one 120 mg oral pills three times per day with food for a total of 4 per day) which allowed for softening of his stool, and the formation of regular bowel movements daily. His stools and bowel function gradually became more regular allowing for a reduction of dose of the orlistat (to one 120 mg oral pill twice per day with food) as maintenance. This allowed for cessation of the Fleet enemas and the disempaction.
This demonstrates the use of orlistat for the treatment of constipation related to deconditioning/bedridden, but also a progressive increase in dose to allow for good bowel function and then titration to lower long term effective dosing.
All citations referred to herein are hereby incorporated by reference.
