US 2006007.9514A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0079514 A1 Preston (43) Pub. Date: Apr. 13, 2006

(54) METHODS AND COMPOSITIONS Publication Classification INCLUDING METHSCOPOLAMINE BROMIDE (51) Int. Cl. (75) Inventor: David M. Preston, Chapel Hill, NC A61K 3 I/5513 (2006.01) (US) A6II 3 L/46 (2006.01) A6II 3/44 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/221; 514/304: 514/357 HUTCHISON & MASON PLLC PO BOX 31686 RALEIGH, NC 27612 (US) (57) ABSTRACT (73) Assignee: Victory Pharma Incorporated Therapeutic pharmaceutical compositions are provided that Appl. No.: 11/001,748 include an agent and a sedative agent. Par (21) ticularly preferred anticholinergic agents include anticholin (22) Filed: Dec. 2, 2004 ergic agents which do not substantially cross the blood-brain barrier. Methscopolamine bromide is the preferred anticho Related U.S. Application Data linergic agent. The sedative agent may be hydrochloride or diazepam. Various methods using the com (63) Continuation-in-part of application No. 10/964.252, positions to alleviate gastrointestinal disorders or symptoms filed on Oct. 13, 2004. thereof are also provided. US 2006/007.9514 A1 Apr. 13, 2006

METHODS AND COMPOSITIONS INCLUDING tract disorders or symptoms thereof and methods for admin METHSCOPOLAMINE BROMIDE istration of the therapeutic pharmaceutical compositions are still needed. Thus, there is still a need in the art for a CROSS-REFERENCE TO RELATED formulation of anticholinergic agents which is Substantially APPLICATIONS free of the disadvantages, defects and limitations of the formulations disclosed in the art. 0001. This is a continuation-in-part application of U.S. patent application Ser. No. 10/964,252, filed Oct. 13, 2004, SUMMARY the entire contents of which are hereby incorporated herein by reference. 0007. In accordance with the foregoing, there are pro vided by the embodiments of the present invention thera FIELD peutic pharmaceutical preparations consisting essentially of 0002 The present invention is directed to therapeutic a therapeutically effective amount of an anticholinergic agents for the treatment of gastrointestinal disorders and agent and a sedative agent whereby the combination of methods for administering those agents. The invention gen anticholinergic agent and sedative agent alleviates one or erally relates to therapeutic pharmaceutical compositions more gastrointestinal disorders or one or more symptom including an anticholinergic agent and a sedative agent. The thereof. therapeutic pharmaceutical compositions may be used in 0008. In one embodiment, a therapeutic pharmaceutical methods for treating gastrointestinal tract disorders or con composition is provided consisting essentially of a thera ditions or symptoms of Such disorders or conditions. peutically effective amount of a blended mixture of an anticholinergic agent comprising methScopolamine bromide BACKGROUND and a sedative agent comprising chlordiazepoxide hydro chloride. In a preferred embodiment, the ratio of the meth 0003 Anticholinergic agents are typically antagonistic to bromide to the chlordiazepoxide hydrochloride the action of parasympathetic or other nerve is about 0.5:1 to about 1:1. In another preferred embodiment, fibers. Generally, anticholinergic agents block or inhibit the the methScopolamine bromide is present in an amount of effects of which is produced by the body and about 2.0 to about 5.0 mg per dose (about 8.0 mg to about is responsible for certain nervous system activities. Various 20.0 mg per day) and the chlordiazepoxide hydrochloride is anticholinergic compounds are known which have a variety present in an amount of about 5.0 mg per dose (about 20.0 of effects on the human body depending on the particular mg per day). The therapeutic pharmaceutical composition structure of the compound. Anticholinergic agents derived preferably is administered orally in an immediate release from the belladonna alkaloids may produce a number of form given four times a day or is in a Sustained release effects in the body, including relief from spasms of the preparation given less than four times a day, and is available gastrointestinal tract, the bladder and the biliary tract. Bel in powder form for delivery to a patient in need of the ladonna alkaloid anticholinergic compounds include the therapeutic pharmaceutical composition. tertiary amines , and Scopolamine, which are believed to cross the blood brain barrier and exert 0009. In another embodiment, a therapeutic pharmaceu an effect on the central nervous system. The effects on the tical composition is provided consisting essentially of a central nervous system may be a negative consequence of therapeutically effective amount of a blended mixture of an the use of these anticholinergic compounds, causing a vari anticholinergic agent comprising methScopolamine bromide ety of unwanted side effects. and a sedative agent comprising diazepam. In a preferred embodiment, the methScopolamine bromide is present in an 0004 Quaternary ammonium anticholinergic agents have amount of about 2.0 to about 5.0 mg per dose (about 8.0 mg been derived from the belladonna alkaloids by such modi to about 20.0 mg per day) and the diazepam is present in an fications as, for example, by the addition of a second methyl amount of about 2.0 to about 5.0 mg per dose (about 8.0 mg group to the nitrogen. Such quaternary ammonium anticho to about 20.0 mg per day). The therapeutic pharmaceutical linergic agents are believed to not cross the blood brain composition preferably is administered orally in an imme barrier, and, thus, do not exert the same effect on the central diate release form given four times a day or is in a Sustained nervous system as the belladonna alkaloids from which release preparation given less than four times a day, and is these compounds may be derived. available in powder form for delivery to a patient in need of 0005 Clidinium bromide is a quaternary ammonium the therapeutic pharmaceutical composition. anticholinergic agent. It has been used in LibraxTM, which 0010. In yet another embodiment, a method of alleviating contains clidinium bromide and chlordiazepoxide hydro at least one gastrointestinal disorder or at least one symptom chloride, a benzodiazepine. LibraxTM has been prescribed of a gastrointestinal disorder in a human patient is provided, for the treatment of a variety of gastrointestinal disorders the method comprising administering to the patient a thera Such as peptic ulcer, irritable bowel syndrome and acute peutic pharmaceutical composition consisting essentially of enterocolitis. The Food and Administration, FDA, a therapeutically effective amount of a blended mixture of however, has questioned the effectiveness of this compound. methScopolamine bromide and chlordiazepoxide hydrochlo In addition, while clidinium bromide may not have the ride. In a preferred embodiment, the ratio of the methsco effects of the belladonna alkaloids on the central nervous polamine bromide to the chlordiazepoxide is about 0.5:1 to system, it is postulated that clidinium bromide has the about 1:1. In another preferred embodiment, the methsco potential to cause liver toxicity in some patients. polamine bromide is present in an amount of about 2.0 to 0006. In view of the foregoing, therapeutic pharmaceu about 5.0 mg per dose (about 8.0 mg to about 20.0 mg per tical compositions useful for the treatment of gastrointestinal day) and the chlordiazepoxide hydrochloride is present in an US 2006/007.9514 A1 Apr. 13, 2006 amount of about 5.0 mg per dose (about 20 mg per day). The of active ingredient deemed necessary in the formulation to therapeutic pharmaceutical composition preferably is provide the desired amount upon administration. administered orally in an immediate release form given four 0017 “Available for immediate delivery” means the times a day or is in a Sustained release preparation given less therapeutic pharmaceutical composition is provided in a than four times a day, and is available in powder form for formulation allowing the blended mixture of anticholinergic delivery to a patient in need of the therapeutic pharmaceu agent and sedative agent to begin acting in a therapeutic tical composition. manner Substantially as soon as the agents become available 0011. In yet a further embodiment, a method of alleviat in the body and/or bloodstream of the patient. ing at least one gastrointestinal disorder or at least one 0018 “Sustained release” means the therapeutic pharma symptom of a gastrointestinal disorder in a human patient is ceutical composition is provided in a formulation Such that provided, the method comprising administering to the the composition provides an initial therapeutic effect and patient a therapeutic pharmaceutical composition consisting also an ongoing or additional therapeutic release of thera essentially of a therapeutically effective amount of a blended peutic pharmaceutical composition or therapeutic effect over mixture of methScopolamine bromide and diazepam. In a preferred embodiment, the methscopolamine bromide is a desired period of time. present in an amount of about 2.0 to about 5.0 mg per dose 0019 “Substantially no liver toxicity” means that a (about 8.0 mg to about 20.0 mg per day) and the diazepam patient ingesting a therapeutic pharmaceutical composition is present in an amount of about 2.0 to about 5.0 mg per dose consisting essentially of an anticholinergic agent and seda (about 8.0 mg to about 20.0 mg per day). The therapeutic tive agent according to embodiments disclosed herein does pharmaceutical composition preferably is administered not experience a Substantial increase in liver enzyme pro orally in an immediate release form given four times a day duction associated with administration of the composition. or is in a Sustained release preparation given less than four 0020) “Anticholinergic compounds include compounds times a day, and is available in powder form for delivery to typically antagonistic to the action of parasympathetic or a patient in need of the therapeutic pharmaceutical compo other cholinergic nerve fibers. sition. 0021 Methscopoloamine bromide is an anticholinergic DETAILED DESCRIPTION agent having the chemical name (1C.2fB.4f.5C.73)-7-(2S)- 3-hydroxy-1-oxo-2-phenylpropoxy-9,9-dimethyl-3-oxa-9- 0012. The present invention relates to methods and com azoniatricyclo3.3.1.0nonane bromide. Methscopoloamine positions for various uses, including the administration of bromide is a quaternary ammonium derivative of the anti anticholinergic agents with one or more sedative agents for cholinergic scopolamine which possesses the peripheral the treatment of disorders or conditions or symptoms thereof actions of the belladonna alkaloids, but does not exhibit the relating to the gastrointestinal tract, including the stomach central actions because of its lack of ability to cross the and/or intestines. It has been found that the deficiencies of blood-brain barrier. Without being bound to any theory, the prior described pharmaceutical formulations of anticho methScopolamine bromide, when administered according to linergic agents for the treatment of gastrointestinal disorders the embodiments disclosed with a sedative agent, is believed and/or symptoms thereof can be overcome by the use of to decrease parasympathetic tone in the gastrointestinal tract methScopolamine bromide as the anticholinergic agent with and slow gastrointestinal motility without Substantial nega particular sedative agents in the pharmaceutical or therapeu tive side effects, thus effectively providing the desired tic formulation. MethScopolamine bromide may, in some therapeutic effect in alleviating gastrointestinal disorders or embodiments, be used in the substantial absence of other symptoms thereof. Methscopolamine bromide is also active agents. Prior to describing this invention in further believed to substantially avoid the potential liver toxicity detail, however, the following terms will first be defined. issues of other quaternary ammonium anticholinergic Definitions agents. 0013 The phrase “alleviating a symptom of a gastrointes 0022. The amount of methscopolamine bromide gener tinal disorder” means reducing or eliminating the severity or ally will be the equivalent of about 8 mg/day to about 20 the frequency of the symptom or both. mg/day. A typical dosage is about 2.0 mg to about 5.0 mg administered four times a day. The preferred dosage is about 0014. The phase “alleviating a gastrointestinal disorder 2.5 mg administered orally four times a day. means reducing or eliminating one or more symptoms 0023 The anticholinergic agent may be administered as suffered by the patient due to one or more condition, illness, the primary active agent or in the Substantial absence of infection, or disease state involving the gastrointestinal tract, other active therapeutic agents, but preferably is adminis including, but not limited to the stomach and/or bowel. tered in combination with a sedative agent as a blended Exemplary gastrointestinal disorders include, but are not mixture of anticholinergic agent and sedative agent. The limited to, ulcer, bowel spasms, abdominal pain, bloating, sedative agent is an agent known to cause a sedating or cramps, inflammation of the stomach and/or intestines, tranquilizing effect on a mammal, i.e., having the capacity to irritable bowel syndrome, inflammatory bowel disease and depress the function of the central nervous system such that the like. calming, relaxation or drowsiness is produced. Sedative 0015. A “disorder includes any condition, illness, dis agents useful in the present therapeutic pharmaceutical ease, infection or the like. compositions may include benzodiazepines, preferably, 0016 “Effective amount” or “therapeutically effective chlordiazepoxide hydrochloride or diazepam. amount’ means the amount needed for the desired thera 0024. The amount of chlordiazepoxide hydrochloride peutic effect and includes any additional amount or overage when used in the pharmaceutical composition typically will US 2006/007.9514 A1 Apr. 13, 2006

be about 5 mg administered four times a day. Thus, the may be used in the treatment of one or more gastrointestinal typical dose will be about 20 mg a day. The amount of disorders or conditions or one or more symptoms thereof. In diazepam when used in the pharmaceutical composition one embodiment, the therapeutic pharmaceutical composi typically will be about 2 to about 5 mg administered four tions may be used to treat conditions or disorders requiring times a day. Thus, the typical dosage of diazepam will be an effect. In a preferred embodiment, the about 8 to about 20 mg a day. The dosages of the sedative therapeutic pharmaceutical compositions are used to treat agent may be adjusted according to the desired effect as is ulcers or irritable bowel syndrome or symptoms of those known in the art. disorders. 0.025 The therapeutic pharmaceutical compositions dis closed may include a number of other components for EXAMPLE obtaining optimal delivery characteristics of the formulation 0030) The invention will be further explained by the depending on the desired method and form of administration following illustrative example that is intended to be non of the therapeutic pharmaceutical composition to a patient. limiting. Such other components typically are known as excipients and the types and amounts to be used are within the skill of 0031 Capsules (100,000) are prepared containing meth the art. The therapeutic pharmaceutical compositions con scopolamine bromide and chlordiazepoxide hydrochloride sisting essentially of an anticholinergic agent and a sedative according to the following formulation: methScopolamine agent may contain one or more excipients. The excipients bromide, USP 2.60 mg per dose (4.0% excess, 0.23 kg may provide desired delivery characteristics, depending on actual amount), 5.00 mg per dose chlordiazepoxide, 160.00 the route of preparation of the therapeutic pharmaceutical mg lactose monohydrate, 5.00 mg talc, USP 30.00 mg composition and the intended method of administration Starch 1500(R). thereof to a patient. Such excipients specifically may include 0032) While the invention has been described in detail disintegrants, lubricants, diluents, binders, and/or coloring and with reference to specific embodiments thereof, it will agents, among others, so long as the excipients do not be apparent to one skilled in the art that various changes and materially affect the basic and novel characteristics of the modifications can be made without departing from the spirit therapeutic pharmaceutical compositions consisting essen and scope of the invention. tially of an anticholinergic agent and a sedative agent. Suitable excipients include, for example, starches such as What is claimed is: partially pregelatinized maize starch, other pregelatinized 1. A therapeutic pharmaceutical composition consisting starch, or celluloses, Suitable lubricants such as magnesium essentially of a therapeutically effective amount of a blended Stearate, calcium Stearate, talc or Stearic acid and/or suitable mixture of an anticholinergic agent comprising methScopo diluents including lactose, among others. Any coloring agent lamine bromide and a sedative agent comprising chlordiaz certified by the FDA may be used, such as FD&C Yellow #6, epoxide hydrochloride. among others. 2. The therapeutic pharmaceutical composition of claim 1, 0026. The therapeutic pharmaceutical compositions con wherein the ratio of the methscopolamine bromide to the sisting essentially of an anticholinergic agent and a sedative chlordiazepoxide hydrochloride is about 0.5:1 to about 1:1. agent may be prepared using methods known in the phar 3. The therapeutic pharmaceutical composition of claim 1, maceutical art. Such methods of preparation, for example, wherein the methScopolamine bromide is present in an may include a direct compression method, a dry granulation amount of about 2.0 mg to about 5.0 mg. method, wet granulation or encapsulation techniques. 4. The therapeutic pharmaceutical composition of claim 1, 0027. The therapeutic pharmaceutical compositions gen wherein the therapeutic pharmaceutical composition further erally are administered systemically and may be adminis includes one or more pharmaceutical excipients. tered in various ways known in the art. Preferably, the 5. The therapeutic pharmaceutical composition of claim 4. compositions are provided to the patient by oral adminis wherein the therapeutic pharmaceutical composition tration. Typically, the composition will be provided in tablet includes lactose, talc and pregelatinized starch. or capsule form. The composition may be provided in an 6. The therapeutic pharmaceutical composition of claim 1, immediate release form or formulated to provide sustained wherein after administration of the therapeutic pharmaceu release of the blend of anticholinergic agent and sedative tical composition to a patient, Substantially no liver toxicity agent. In a preferred embodiment, the therapeutic pharma is observed in the patient. ceutical composition is prepared as a powder in an imme 7. A therapeutic pharmaceutical composition consisting diate release formulation and provided in capsule form for essentially of a therapeutically effective amount of a blended administration to the patient. mixture of an anticholinergic agent comprising methScopo 0028. The amount of anticholinergic agent and sedative lamine bromide and a sedative agent comprising diazepam. agent in the compositions or pharmaceutical formulations 8. The therapeutic pharmaceutical composition of claim 7. administered to a patient may vary depending upon multiple wherein the methScopolamine bromide is present in an factors including, but not limited to, the particular compo amount of about 2.0 to about 5.0 mg and the diazepam is sition, the patient’s degree of illness, the patients weight, present in an amount of about 2.0 to about 5.0 mg. and the patient's age. The patient may be any mammal in 9. The therapeutic pharmaceutical composition of claim 7. need of treatment for a gastrointestinal disorder or symptom wherein the pharmaceutical composition further includes of a gastrointestinal disorder. Preferably, the patient is a one or more pharmaceutical excipients. human patient. 10. The therapeutic pharmaceutical composition of claim 0029. The pharmaceutical compositions consisting 9, wherein the pharmaceutical composition includes lactose, essentially of an anticholinergic agent and a sedative agent talc and pregelatinized Starch. US 2006/007.9514 A1 Apr. 13, 2006

11. The therapeutic pharmaceutical composition of claim 20. The method of claim 16 wherein the methscopolamine 7, wherein after administration of the therapeutic pharma bromide is present in an amount of about 2.0 mg to about 5.0 ceutical composition to a patient, Substantially no liver ng. toxicity is observed in the patient. 12. A therapeutic pharmaceutical composition consisting 21. The method of claim 16, wherein the gastrointestinal essentially of a therapeutically effective amount of a blended disorder is an ulcer or irritable bowel syndrome. mixture of methScopolamine bromide and chlordiazepoxide 22. The method of claim 16, wherein after administering hydrochloride wherein the ratio of the methscopolamine the therapeutic pharmaceutical composition to the patient bromide to the chlordiazepoxide is about 0.5:1 to about 1:1. substantially no liver toxicity is observed in the patient. 13. The therapeutic pharmaceutical composition of claim 23. A method of alleviating at least one gastrointestinal 12, wherein the blended mixture further contains lactose, disorder or at least one symptom of a gastrointestinal talc and partially pregelatinized maize starch. disorder in a human patient, the method comprising admin 14. The therapeutic pharmaceutical composition of claim istering to the patient a therapeutic pharmaceutical compo 12, wherein the blended mixture is a powder for immediate sition consisting essentially of a therapeutically effective release. amount of a blended mixture of methscopolamine bromide 15. The therapeutic pharmaceutical composition of claim and diazepam. 12, wherein the blended mixture is in a sustained release 24. The method of claim 23, wherein the methscopola formulation. mine bromide is present in an amount of about 2.0 to about 16. A method of alleviating at least one gastrointestinal 5.0 mg and the diazepam is present in an amount of about disorder or at least one symptom of a gastrointestinal 2.0 to about 5.0 mg. disorder in a human patient, the method comprising admin 25. The method of claim 23, wherein the therapeutic istering to the patient a therapeutic pharmaceutical compo pharmaceutical composition is administered orally in an sition consisting essentially of a therapeutically effective immediate release form four times a day. amount of a blended mixture of methscopolamine bromide 26. The method of claim 23, wherein the therapeutic and chlordiazepoxide hydrochloride. pharmaceutical composition is administered orally in a 17. The method of claim 16, wherein the ratio of the Sustained release formulation given less than four times a methscopolamine bromide to the chlordiazepoxide is about day. 0.5:1 to about 1:1. 18. The method of claim 16, wherein the therapeutic 27. The method of claim 23, wherein the gastrointestinal pharmaceutical composition is administered orally in an disorder is an ulcer or irritable bowel syndrome. immediate release form four times a day. 28. The method of claim 23, wherein after administering 19. The method of claim 16, wherein the therapeutic the therapeutic pharmaceutical composition to the patient pharmaceutical composition is administered orally in a substantially no liver toxicity is observed in the patient. Sustained release formulation given less than four times a day.