WO2008019070A2

WO2008019070A2 - Pharmaceutical compositions of trospium for treating smooth muscle hyperactivity disorders

Info

Publication number: WO2008019070A2
Application number: PCT/US2007/017353
Authority: WO
Inventors: Ebrahim Versi
Original assignee: Ebrahim Versi
Priority date: 2006-08-04
Filing date: 2007-08-03
Publication date: 2008-02-14
Also published as: WO2008019070A3

Abstract

Pharmaceutical compositions and methods are disclosed using trospium and/or its metabolites, and pro-drugs with antimuscarinic smooth muscle relaxant properties, administered as a subcutaneous injection, implant or other depot preparation for the treatment of urinary incontinence, and other smooth muscle hyperactivity disorders thus avoiding the poor bioavailability of oral administration.

Description

PHARMACEUTICAL COMPOSITIONS OF TROSPIUM FOR TREATING SMOOTH MUSCLE HYPERACTIVITY DISORDERS

BACKGROUND OF THE INVENTION

This invention relates to the compound Trospium and its salts. The most commonly used salt for therapeutic purposes is Trospium Chloride.

The generic name Trospium Chloride (CAS-10405-02-4; INN) refers to an anticholinergic compound with the chemical name 3-α-hydroxy-spiro[l-α-H,5-α-H- nortropane-8,r-pyrrolidinium] chloride benzilate; C₂₅ H₃₀ ClNO₃ ; MW=427.97. In this document, the name trospium refers to Trospium Chloride except where other salts are referenced.

The synthesis of trospium was described by Pfleger R. et al. in U.S. Pat. No. 3,480,626 and by Bertholdt H. et al. in Arzneimittel-Forsch, 1967, 17: 719-726. The preclinical pharmacology and toxicology of trospium was described by Antweiler H. in Arzneimittel-Forsch, 1966, 16:1581-1591.

Trospium may be purchased from Galen Ltd, Craigavon, UK or from Madaus AG, KoIn, Germany. Trospium can also be extracted from tablets SPASMOLYT (trospium chloride manufacturer: Hoyer-Madaus, Monheim, Germany) available in Germany, using methods commonly known to those skilled in the art.

Trospium has several known metabolites, the most well known being the spiroalcohol, which is a metabolite formed by ester hydrolysis. The spiroalcohol metabolite has antimuscarinic activity that may contribute to the therapeutic activity of trospium.

Since trospium is a quaternary amine compound, it has an electronic charge and hence it does not easily cross the blood-brain barrier and has therefore fewer CNS side effects than oxybutynin (Todorova A., et al., J. Clin. Pharmacol. 2001, 41: 636-644). However, because of its electronic charge, its absorption through the gastrointestinal (GI) tract is poor (bioavailability of 1-10%) and erratic, thus limiting absorption by the oral route even in formulations designed to be slow or extended release in nature.

Trospium is partially metabolized in the liver by esterification and also excreted (60%) unchanged by renal tubular excretion. It is not metabolized by the cytochrome P450 enzyme system and thus the risk of drug-drug interaction is limited. In addition the drug does not cause cardiac abnormalities such as QT prolongation.

Specifically, the present invention relates to the mode of administration as a subcutaneous injection or implant to avoid the oral route. This applies to the therapeutic use of trospium and the active metabolites thereof and pro-drug formulations, and pharmaceutical compositions containing at least one of said compounds for treating smooth muscle hyperactivity disorders. Examples of such diseases include but are not limited to urinary, gastrointestinal and respiratory disorders. These include urinary incontinence, detrusor overactivity, urinary urgency and frequency and gastrointestinal disorders, including gastrointestinal hyperactivity, diarrhea, irritable bowel syndrome, and respiratory disorders including asthma and chronic obstructive pulmonary disease and related disorders, and other smooth muscle hyperactivity disorders.

SUMMARY OF THE INVENTION

The present invention provides a method for treating smooth muscle hyperactivity disorders in a mammal comprising administering to said mammal a therapeutically effective amount of trospium and/or its metabolite and/or its pro-drug as a pharmaceutically acceptable salt in a subcutaneously or intramuscularly injectable form, or a subcutaneously implantable material. DETAILED DESCRIPTION OF THE INVENTION

As noted, the efficacy of trospium administered orally is limited by its low bioavailability. The present invention provides subcutaneously injectable or implantable formulations of trospium which will avoid limitations of oral administration and provide more efficacious and longer lasting therapy for smooth muscle hyperactivity disorders.

Smooth muscle hyperactivity disorders are treated with antimuscarinic agents as they do not have anticholinergic effects on nicotinic receptors. The most common condition treated with the use of such agents is overactive bladder. This is a condition characterized by urinary urgency, frequency and in about half of cases with urinary incontinence. A related and more severe condition is detrusor overactivity which results from neurological impairment of the bladder. Commonly used compounds for these conditions within the class of antimuscarinic drugs include trospium, oxybutynin, tolterodine, solifenacin and darifenacin. All these compounds are effective but their overall efficacy is short of optimal and this may be related to compliance difficulties of daily oral administration. In the future there may be an increased use of this class of compounds for other non-urological smooth muscle hyperactivity disorders.

Gastrointestinal (GI) motility is mediated by muscarinic receptors and consequently antimuscarinic agents will have an effect on this. Thus overactive GI disorders such as irritable bowel syndrome and related disorders such as chronic diarrhea can be helped by such therapy.

Asthma is a result of constriction of the smooth muscle of the branches of the bronchial tree and this too is mediated by muscarinic receptors. Consequently therapeutic inhibition of this constrictive effect with antimuscarinic agents is also beneficial.

The conditions noted above are all chronic and require long term therapy. Unfortunately, effectiveness of therapy is confounded by poor compliance as daily oral administration is difficult for patients to remember and is not without a significant degree of inconvenience. Thus a therapy that does not need to be administered daily would be attractive and offer greater effectiveness in some patients. This goal can be achieved by subcutaneous depot instillations of antimuscarinic agents where slow release into the blood stream will result in long lasting therapy.

Trospium has been shown to reduce bladder hyperactivity in patients suffering from urinary incontinence and exerts spasmolytic effects on the bladder by inhibiting the effects of acetylcholine on smooth muscle. Trospium has selectivity for muscarinic receptors over nicotinic receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions. Trospium does not have selectivity of any specific muscarinic receptor subtype but has a higher affinity for these receptors than compounds within the class of antimuscarinic drugs for urinary incontinence, including oxybutynin, tolterodine, solifenacin or darifenacin. Active metabolites of trospium exert antimuscarinic activities that may account for part of the therapeutic activity of trospium.

Trospium use is not associated with increase in QT-interval in humans, which confers less risk of cardiac problems with its use. Patients suffering from the disease called Long QT Syndrome should not use medication that may cause further prolongation of the QT- interval of the ECG, but may be able to use trospium without aggravating their preexisting risk for torsades de pointes cardiac arrhythmias.

Trospium to some degree undergoes hepatic metabolism, resulting in the formation of the spiroalcohol, which is an active (antimuscarinic) metabolite formed by ester hydrolysis. In contrast, oxybutynin, tolterodine, darifenacin and solifenacin (Postlind et al, Lukkari et al., Andersson) all undergo extensive P450-mediated metabolism.

The effects of trospium on CYP 450-induced metabolism of various drugs has been investigated, using human liver microsomes enzymes and drugs that are metabolized by known P450 enzymes. The CYP 2D6-mediated metabolism of 3-[2-N,N-diethyl-N- (methyl-ammonium) ethyl]-7-methoxy-4-methyl-coumarin was inhibited by trospium with an IC50 value of about 20 .mu.M, which is significantly higher than the expected therapeutic plasma concentration of trospium that is in the range of a few nM. Trospium had even more negligible inhibitory effects on drug metabolism by CYP3 A4. As pointed out above, it has been found that tolterodine and oxybutynin potently inhibit both CYP 2D6 and CYP 3A isoenzyme metabolism. Metabolic inhibition of this type is known to increase the concomitant liability of cardiac arrhythmias of drugs that cause QT- prolongation (Woosley et al. JAMA 1993, 269: 1532-1536). These data suggest that trospium will not cause this type of drug interaction. Trospium could therefore be administered together with drugs like ketoconazole, itraconazole or erythromycin without enhanced risk for cardiac arrhythmias caused by QT-prolongation.

While trospium is a very safe drug and has been in human use for over 10 years, its clinical efficacy has not been shown to be better than that of other antimuscarinic agents referenced above despite its higher affinity for the muscarinic receptor. This might be because of its erratic and suboptimal GI absorption characteristics. By injecting or implanting a depot preparation of the drug or its metabolites into the subcutaneous space, the difficulties of oral administration are overcome.

Depot preparations of trospium and/or its metabolite can be constructed in many different ways. A simple form would be a suspension formulation of a poorly soluble salt of trospium and/or its metabolite and this could be injected into the subcutaneous space preferably into adipose tissue where it would serve as a depot reservoir for slow release. The release characteristics would depend upon among other variables, the dose, volume and site of injection. While simple, the downside of such a method is that the depot could not be readily removed.

Another approach would be the use of a pro-drug of trospium which would be administered as a depot preparation but which would slowly be metabolized to the active form of trospium and this would be pharmacologically active and more soluble. This active form of trospium would then be systemically available to exert its action.

A more favorable approach would be the use of a biodegradable implant material that would contain the drug as a pharmaceutically acceptable salt in such a way as to allow release over a prolonged period. The implant would be inserted subcutaneously into the fat layer using a local anesthetic with or without a trochar system. This would be sited in a subcutaneous region of the body with an adequate adipose layer such as the abdomen, buttocks or thigh. The system would allow steady state release of drug over an extended period, preferably longer than 90 days. Should the clinical situation warrant, the implant could be surgically removed to prevent further release of the drug.

The present invention is not limited to any particular method of depot trospium and/or its metabolite or pro-drug formulations nor is it limited to any particular salt. Also the depot preparation could contain other pharmacologically or biologically active compounds to aid the therapeutic endeavor. No known reference teaches or enables the methods of the present invention comprising administering trospium and/or its metabolites or pro-drugs to a human by a depot subcutaneous injection or implant for prolonged therapy by long term sustained release; nor do the published references alone or in combination suggest these methods.

The pharmaceutical compositions of the present invention comprise of trospium and/or a metabolite or pro-drug thereof as the active ingredient, or any pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.

The terms "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric, and the like. The chloride is particularly preferred.

Poorly soluble salts of trospium could be prepared from aralkyl esterified-hydroxyacids such as palmitoyloxy-acetic acid, benzyl-hemisuccinate and related compounds where the length of the aralkyl group could be used to alter the solubility of the salt and hence prolong the duration of action.

The compositions of the present invention include suspensions, solutions, elixirs or solid dosage forms. Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used as required to facilitate optimal release characteristics and longevity. Similarly the dosage forms employed would depend on the desired plasma pK characteristics.

A preferred embodiment of the present invention is the packaging of the drug or combination of drugs including trospium and/or its metabolite into a biodegradable implant that is inserted, possibly with a trochar mechanism into the fat layer in the subcutaneous space. Preferred regions include but are not limited to the abdomen, buttocks and thigh where there is an adequate adipose layer to house the implant without discomfort to the patient. Such an implant would allow defined pK characteristics ideal for the therapeutic purpose and long lasting effect of the therapy. In addition, should the clinical scenario warrant, the implant could be surgically removed and further release of the pharmacological agent stopped.

Claims

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically active amount of trospium, or a salt or metabolite thereof, in a subcutaneously or intramuscularly injectable suspension.

2. A pharmaceutical composition of claim 1 , wherein the pharmaceutically salt of trospium is an acetic or derivative of acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, or tartaric salt thereof.

3. A pharmaceutical. composition of claim 1, wherein the suspension comprises a pharmaceutically acceptable starch, sugar, or microcrystalline cellulose.

4. A pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

5. A pharmaceutical composition comprising a pharmaceutically active amount of a prodrug of trospium, or a salt or metabolite thereof, in a subcutaneously or intramuscularly injectable suspension.

6. A pharmaceutical composition of claim 5, wherein the suspension comprises a pharmaceutically acceptable starch, sugar, or microcrystalline cellulose.

7. A pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

8. A pharmaceutical composition comprising a pharmaceutically active amount of trospium, or a salt or metabolite thereof, in a subcutaneously implantable material.

9. A pharmaceutical composition of claim 8, wherein the pharmaceutically salt of trospium is an acetic or derivative of acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, or tartaric salt thereof.

10. A pharmaceutical composition of claim 8, wherein the subcutaneously implantable material comprises a solid, crystal, or pharmaceutically active trospium contained in a biodegradable capsule.

11. A pharmaceutical composition of claim 8, further comprising a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

12. A pharmaceutical composition comprising a pharmaceutically active amount of a prodrug of trospium, or a salt or metabolite thereof, in a subcutaneously implantable material.

13. A pharmaceutical composition of claim 12, wherein the subcutaneously implantable material comprises a solid, crystal, or pharmaceutically active prodrug of trospium contained in a biodegradable capsule.

14. A pharmaceutical composition of claim 12, further comprising a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

15. A method for treating a smooth muscle hyperactivity disorder in a patient comprising subcutaneously administering to said patient a composition comprising a therapeutically effective amount of trospium, or a salt or metabolite thereof, or pro-drug thereof, in a subcutaneously or intramuscularly injectable suspension.

16. A method of claim 15, wherein the suspension comprises a pharmaceutically acceptable starch, sugar, or microcrystalline cellulose

17. A method of claim 15, wherein the suspension further comprises a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

18. A method of claim 15, wherein the smooth muscle hyperactivity disorder is overactive bladder, detrusor overactivity, neurogenic bladder, urinary urge incontinence, irritable bowel syndrome, spastic colon, irritable colon, mucus colitis, chronic diarrhea or associated disorder, asthma, or chronic obstructive pulmonary disease or related disorder.

19. A method for treating a smooth muscle hyperactivity disorder in a patient comprising subcutaneously administering to said patient a composition comprising a therapeutically effective amount of trospium, or a salt or metabolite thereof, or a pro-drug thereof, in a subcutaneously implantable material.

20. A method of claim 19, wherein the subcutaneously implantable material comprises a solid, crystal, or pharmaceutically active trospium contained in a biodegradable capsule.

21. A method of claim 19, wherein the implantable material further comprises a pharmaceutically acceptable diluent, granulating agent, lubricant, binder, or disintegrating agent.

22. A method of claim 19, wherein the smooth muscle hyperactivity disorder is overactive bladder, detrusor overactivity, neurogenic bladder, urinary urge incontinence, irritable bowel syndrome, spastic colon, irritable colon, mucus colitis, chronic diarrhea or associated disorder, asthma, or chronic obstructive pulmonary disease or related disorder.