METHOD FOR CONTROLLING GASTROINTESTINAL DYSMOTILITY

Abstract: Method for controlling gastrointestinal dysmotility in humans by administration of opioid antagonists.

Description: METHOD FOR CONTROLLING GASTTOΩ-πΕSTINAL DYSMOTILITY DESCRIPTION OF THE PRIOR ART Gastrointestinal dysmotility affects many humans and is associated, with various clinical signs and syndromes . Hypomotil¬ ity is associated with chronic constipation, obstipation, idio- pathic abdominal distention, abdominal pain, abdominal cramps , • irritable bowel syndrome, non-tropical sprue, megacolon associated with hypothyroidis , pseudo-obstruction of the gastrointestinal tract, colitis, hypomotility of the colon associated with diabetes mellitus , adult onset Hirschsprung ' s disease, neurological dis¬ orders, yopathic disorders, geriatric hypomotility disorders, j ejunal-ileal bypass with secondary megacolon, hypomotility associated with cancer chemotherapy, hypomotility associated with severe bums and other major stresses, hypomotility associated with syndromes of depression, post-operative intestinal distension, and other pathological conditions . Gastrointestinal hypomotility disorders also include other disorders of esophogeal and gastric-mo ility and gastric emptying disorders such as diabetic gastric paresis, scleroderma and other disord ers . Id opathic constipation is a major health problem which affects many individuals. Millions of persons utilize laxatives, stool sof teners, fiber preparations, mineral oil, gas absorb- ants, suppositories or enemas on a continuous basis . Partial hypomotility is a major feature of several defined gastrointes¬ tinal disorders. Hypomotility is often associated with recurring bouts of hypermotility, the so-called intermittent hypomotility-hyper- motility syndrome. Clinical manifestations of this affliction include alternate bouts of constipation and diarrhea, abdominal distention, pains and cramps, ileitis, regional enteritis, generalized irritable bowel syndrome, irritable colon, syndrome, ulcerative and other forms of colitis. Opioid antagonists are a well recognized class of chemical agents. They have been described in detail in the scientific and patent literature. Pure opioid antagonists are agents which specifically reverse the effects of opioid agonists, bind to specific opioid receptors but have no opioid agonist activity. This invention is concerned with the use of pure opioid antagonists in contrast to opioid agonists and agents that manifest mixed agonist-antagonist activities such as pentazocine, buprenorphine and others. THE IWEKTION It has now been discovered that human disorders related to gastrointestinal dys otility in humans can be improved, thereby alleviating the above noted illnesses, by administration of therapeutically effective amounts of pure opioid antagonists such as naloxone, naltrexone, nalmefene and related compounds. The pharmaceutically active product will normally be admin¬ istered orally or parenterally. In some cases both routes may be employed either sequentially or simultaneously. The dosage regimen which has been found to be most effective is about 2 to 70 mg per day. The preferred dosage for oral administration is about 10 to 50 mg per day, and for parenteral administration about 10 to 70 mg per day. For sustained release forms of the medicament, either oral or parenteral dosage forms are useful which deliver 10 to 50 mg per day. Of course sustained release forms can be prepared which will deliver proportional amounts over selected periods of time, for example 4, 6 or 12 hours. These quantities, irrespective of the method or route of admin¬ istration selected, appear to provide optimum relief for adults in the 60 to 70 kg weight class. The attending physician may choose to vary the defined quantities depending on such factors as the condition being treated, and the age, weight, and general physical condition of the patient. The principal and preferred compounds which are the subject matter of this invention are naloxone, naltrexone and nalmefene. • These compounds are known narcotic antagonists. They are gen¬ erally recognized as pure opioid antagonists and will be so re¬ garded for purposes of this description. Naltrexone, however, has been described as having slight agonistic activity. Wikler, A., Int. J. of the Addictions 12(7) 869, 1977. It should be noted, and is here emphasized, that the opioid antagonists as used in this invention are not used to neutralize the effect of opioid agonists such as narcotic drugs. They are used to treat clinical gastroenterologic disorders in which in- testinal dys otility is a major component. For such use they may be employed to treat intermittent or prolonged periods of hypomotility or intermittent hypomotility-hypermotility. It has now been discovered that hypomotility arises from relative or absolute excess of one or more of the endogenous opioids at the intestinal level, in the brain or at both sites, or from abnormal binding of those endogenous opioids to their spe- cific receptors in the intestine and/or brain, thereby causing inhibition of propulsive intestinal contractions. The use of pure opioid antagonists in accordance with this invention restores normal endogenous opioid balance and alleviates άysmotility problems. Some humans, such as those suffering from chronic consti¬ pation, are affected with chronic hypomotility. Some individuals may suffer from hypermotility at one time and hypomotility another. As indicated above, the effect of the therapeutic agents of this invention when used as described herein is to restore the balance between available and bound opiate receptor sites thereby to restore normal motility as evidenced by relief of constipation, relief of abdominal distention or pain as illustrated in the examples. Naloxone, naltrexone and na nefene are representatives of known classes of compounds which are pure opioid antagonists. The compounds of the class are derivatives of morphine and codeine. * Nalmefene is typical of one useful class of compounds which are described together with their method of preparation in United States Patent 3,896,226 which was issued on July 22, 1975. The compounds are morphine or codeine derivatives which may be represented by the formula: wherein R is allyl or cyclopropylmethyl, R, is hydrogen or Q hydroxy and „ is hydroxy or methoxy. Typical compounds within the scope of the formula include: . 6-methylene-6-desoxy-N-allyl-14-hydroxydihydronor- morphine. b. 6-methylene-6-desoxy-N-cyclopropylaethyl-14-hydroxydihy- dronormorphine. c. 6-methylene-6-desoxy-N-cyclopropylmethyl dihydronor- morphine. d. 6-methylene-6-desoxy-N-allyl-dihydronormorphine. a. 6-methylene-6-desoxy-N-allyl-dihydronorcodeine. f. 6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihy- dronorcodeine. g. 6-methylene-6-desoxy-N-allyl-14-hydroxydihydronor- codeine. Compound b_ is nalmefene. The compounds are prepared by reaction of the appropriate 6-keto starting compound with excess triphenylphosphomethylene followed -by reaction with an allyl or cyclopropylmethyl halide, O PI suitably the bromide or chloride. If the starting compound is a 3-hydroxy compound, i.e., a morphine derivative, the final pro¬ duct can be converted to a codeine derivative by reaction with diazomethane to convert the hydroxyl group to a methoxyl moiety. Other morphine derivatives which may be employed in the practice of the invention as well as methods for their prepara¬ tion are described in United States Patents 3,254,088 and 3,332,950. They may be represented by the formula: wherein Rg is allyl, 3'-methyl-2*-butenyl, cyclopropylmethyl or cyclobutylmethyl. The compounds may be prepared by reaction of a selected 14-hydroxy starting compound with a suitable organic halide such as l-bromo-3-methyl-2-butene, allyl bromide or the corresponding chlorides. Typical compounds within the scope of the foregoing formula include: a. N-ally1-14-hydroxydihydronormorphinone. b. N-cycloproρylmethyl-14-hydroxydihydronormorphinone. c. N-cyclobutylmethy1-14-hyd oxydihydronormorphinone. d. N-(3*methyl-2-butenyl)—14-hydroxydihydronormorphinone. OMH The first named compound is naloxone. The.second is naltrexone. A third class of pure antagonists useful in this invention is described along with methods of preparation in United States Patent 3,320,262. The compounds are represented by the formulas shown below in which the second formula represents dihydro wherein R^is methoxy or hydroxy, R j is hydrogen or hydroxy and Rg is hydrogen, methyl, ethyl, propyl, allyl or benzyl. Typical compounds within the scope of the formula include: a. N-cyclopropylmethyl-nor-14-hydroxycodeinone-6-carboxy- methyloxime. OMP - - - — " ' ~ " ' -8- b. N-cyclopropylmethyl-nor-codeinone-6-carboxymethyloxime. c. N-cyclopropylmethyl-nor-14-hydroxymorphinone-6-carboxy- ethyloxime. d. N-cyclopropyimethyl-nor-morphiήone-6-carboxymethyloxime 5 methylester. •a. N-cyclopropylmethyl-nor-14-hydroxydihydrocodeinone-6- carboxy-methyloxi e. f. N-cyclopropylmethyl-nor-14-hydroxydihydrocodeinone-6- carboxy-methyloxime methylester. 10 g. N-cyclopropylmethyl-nor-dihydrocodeinone-6-carboxy- methyloxime methylester. h. N-cyclopropylmethyl-nor-14-hydroxydihydromorphinone-6- carboxy-meth loxi e methylester. i. N-cyclopropylmethyl-nor-dihydromorphinone-6-carboxy- 15 methyloxime methylester. The compounds are prepared by reaction of the selected ketone starting compound with a suitable organic halide as des¬ cribed above, followed by reaction of the N-substituted compounds with a selected ester of carboxymethoxyl amine. 20 All of the compounds described above can be utilised in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts which are free of toxicity or other therapeutically harmful or undesirable effects. These include, - for example, such salts as the hydrochloride, hydrobromide, 25 neutral and acid fumarate and maleate, teraphthalate, ethane sulfonate, oxalate and bitartrate. Water-soluble salts with volatile acids (e.g.. hydrochloric and acetic acid) can be prepared by adding an aqueous solution of slightly more than one equivalent of the " ,acid to an aqueous dispersion of the base and evaporating the solution thus formed under reduced pressure. The residue can then be recrystallized. Salts of non-volatile inorganic acids (e.g. orthophosphoric acid) can be prepared by adding the stoichiometric amount of the acid to an aqueous dispersion of the base and treating the resulting solution in the same way. Salts of organic acids which are difficultly soluble in water (e.g. the benzoate) can be pre- pared by reacting the acid and the base in equivalent amounts in ethyl alcohol medium and evaporating the solution. For ease of administration it is, of course, preferred to treat patients orally. Surprisingly, as is illustrated herein¬ after, naloxone, which has been art recognized as being * ρoorly absorbed when given perorally is nevertheless active at local intestinal sites and effective for the indications mentioned above when administered orally. In the event that the patient is unable to cooperate, is kept in a "nothing by mouth" status, if there is an intransigent blockage of the gastrointestinal tract, or if antagonist activity at the brain or at other sys¬ temic sites is desired, the route of choice will be the parenteral route. The principal aspects of the invention, then, are the use of certain known compounds to achieve control of intestinal motility. The compounds may be used alone or in association with selected pharmaceutical carriers in the form of pharmaceutical compositions containing effective amounts of the active agents. — ---'-^ - „_ - - . _ 10 _ The compositions may be administered parenterally or by various non-parenteral routes, primarily oral, but also by buccal, sub- lingual, rectal and transdermal routes. The compositions may be prepared for relatively rapid absorption or in sustained release 5 forms. For buccal and sublingual administration the active in¬ gredient can be formulated in tablet form with water soluble binding agents such as lactose or other palatable carbohydrates. For rectal administration suppositories or inserts con- 10 taining the active ingredient dispersed in such reagents as cocoa butter, petroleum, or other natural lubricant or in a syn¬ thetic emmolient such as polyethylene glycol 1000 or polyethyl¬ ene glycol 4000. Transdermal administration will normally be from a sustained 15 release preparation which may be applied as a patch or from a gauze applied to the skin. The preferred method of administering the active agents of this invention is from sustained release forms since this is most convenient for patients, and avoids the necessity of con- 20 stant clock watching or interruption of normal daily activities. A number of compositions suitable for such preparations are known and can be used in the practice of this invention. As afore¬ said, the dosage forms can be prepared to deliver 10 to 50 mg of active ingredient per day divided over selected time intervals, 25 __ for example 4, 6, 12 or even twenty-four hours. One convenient procedure is to formulate the selected motil¬ ity control agent in a time disintegrating tablet or pelle coated with various thicknesses of known materials such as car- nauba wax, cellulose esters and ethers, fats, keratin, gluten or various natural or synthetic esters. Tablets in which the motility control agent is contained in a slowly dissolving core such as a core of stearic acid or castor oil are useful. Mixed release granule tablets comprising mixtures of the drug itself and the drug in separate particles coated with materials which dissolve, at different rates such as dehydrogenated castor oil or fatty acids can also be employed. Alternatively the active material can be bound to an ion exchange resin such as sulfuric acid type cation exchange resin. The presently preferred sustained release forms of this invention are those in which the active agent is carried through the gastrointestinal tract in a mixed polymer carrier. The carrier slowly erodes during transport so that increments of the opioid antagonist may be released for attachment to receptor sites. In these forms, the principal carrier is a mixed, hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at least one is propyl or butyl. This polymer functions as a drug release retardant. Cellulose deriva¬ tives which are substituted with two different alkyl groups are preferred since there is less tendency for such polymers to crystallize. The polymers are prepared by standard alkoxyla- - tion reactions. In case two different alkyl groups are to be substituted, concurrent or successive reactions may be employed. Generally, with such mixed substituents where will be about 50% of each substituent. The presently preferred polymer is propyl hydroxymethyl cellulose. The cellulose derivative is normally hydrated to a degree of from about 5% to 25% by weight, preferably 10% to 20%. A degree of hydration of 15% by weight is especially preferred since it is readily achieved, and provides sustained release forms with excellent properties. To prevent the cellulose polymer from crystallizing and thereby reducing the rate at which the active agent is released, an anticrystallinity agent is added. The function of the agent is to prevent the cellulose polymer from achieving a degree of regulatity at which it will crystallize. The presently preferred anticrystallinity reagents are polyalkylene oxides, such as poly¬ ethylene oxide or other pharmaceutically acceptable analogues. The molecular weight of the oxide may vary from about 100,000 to 10 million with 4 to 5 million being preferred because of ready availability, ease of compounding and efficiency for preventing crystallization. Normally the amount of such agent added will be from about 15% to 30% by weight so that the weight of cellulose product will he from about 70% to 85%. The polymer and selected active agent or agents are com¬ pounded, to form tablets or other standard dosage forms in conventional equipment with any of a number of anti-stick or releasing agents such as magnesium stearate or talc. The amount _ employed is not critical and normally ranges from about 0.5% to 2% by weight. ' ■ — • " ~-' " ~ ' ' ' " " ' ' _i3_ The sustained release dosage forms can be formulated to contain any desired ' quantity of active agent. Typically, a tab¬ let or other form will contain from about 5% to 20% active in¬ gredient and 80% to 95% carrier. As indicated above, they may 5 be prepared to release the selected quantities of opioid anta¬ gonist over time periods of, for example, * from 4 to 12 hours. In the foregoing discussions, all quantities given on a by weight basis are based on the total weight except the degree of hydration of the cellulose derivative which is based on the 10 weight of the derivative. In short, the motility control agents of this invention can be administered in any of a wide variety of forms includ¬ ing tablets, capsules, lozenges, suppositories, emulsions, isotonic solutions and the like. They can be formulated for 15 immediate absorption or for sustained release. The following non-limiting examples are given by way of illustration only. EXAMPLE 1 A female with a history of chronic constipation for a 20 period of over twenty years, requiring daily use of large doses of laxatives plus frequent enemas, was admitted to the research hospital on day one at approximately 4:00 p.m. She was given a standard laxative regimen documented to be inadequate to effect a spontaneous bowel movement, and placed on a high 25 - residue diet. • - - " ~~ * " * ' ~~~ -1 - During the first 24 hours she was treated with a placebo (Infusion A) according to the following schedule: 4 p.m.-5 p.m. 1) Dextrose and water 250 cc over 1 hr. 5 p.m.-12 midnight 2) Saline 250 cc over 7 hrs. 5 12 midnight-8 a.m. 3) Dextrose and water 250 cc over 8 hrs. 8 a.m.-4 p.m. 4) Dextrose and water ' 250 cc over 8 hrs. 1250 cc over 24 hrs. On day two at 4:00 p.m. the placebo was terminated and the patient was treated intravenously with naloxone according to 10 the following schedule. 4pm-5pm l)Dextrose & Water 250 cc + l.δmg Naloxone in 1 hr. 5ρm-12 midnight 2)Saline 250 cc + 8.4mg Naloxone in 7 hrs. 12 midnight-8am 3)Dextroεe & Water 250 cc + 9.6mg Naloxone in 8 hrs. 8am-4pm 4)D-εxtrose S Water 500 cc + 9.6mg Naloxone in 8 hrs. 1250 cc + 29.2mg Naloxone in 24 hrs 15 At 4:00 p.m. on day three the parenteral administration was discontinued and the dosage regimen was changed to oral adminis¬ tration of 3.6 mg of naloxone in synthetic grape juice every three hours for three days, omitting treatment only when the 20 patient was sleeping. The total dosage per day was 21.6 mg. During the five days that the patient was under hospital care the stools were collected and weighed. The results were as follows: ... O ~ WIP -15- STOOL ' WEIGHT GRAMS .22-. Wet Weight- ' Dry Weight 1 452 . 41 2 649 52 3 985 77 4 997 ' 77 5 806 65 Samples of the patient's blood and urine were collected each day and subjected to analysis. No adverse effects were observed. The experiment was conducted as a single blind. The patient was not aware of whether she was receiving a placebo or the active agent. EXAMPLE ' II A second patient with a history of over twenty years of chronic constipation, intractable to laxatives, who for the past several months was only relieved by enema treatment was admitted to * the hospital and placed on a high residue diet. She was then treated in a manner similar to the patient of Example I, but with no laxatives or emenas given, in accordance with the following schedule: Day Treatment 1 29.2 mg naloxone, intravenous 2 placebo, oral 3 14.4 mg naloxone, oral 4 21.6 mg naloxone, oral 5 21.6 mg naloxone, oral 6 7.2 mg naloxone, oral OMPI Day Treatment 7 placebo, oral 8 placebo, oral 9 placebo, oral The patient's stools were collected and weighed each day with the following results: ' STOOL WEIGHT GRAMS Day Wet Weight ' Dry Weight 1 84 18.5 2 none 3 35 8.2 4 125 66.4 5 230 82.4 6 34 12.1 7 none - 8 43 12.2 9 none - No adverse effects were noted by clinical examinations, blood or urine analysis. The following tables summarize the results which were achieved with additional patients treated with nalaxone following the general procedures of Examples I and II. Substantially the same results will be achieved with naltrexone, nalmefene and other compounds within the scope of the foregoing formulas. The tables set forth the significant details and results of a number of studies conducted with different patients suffer¬ ing from various forms of intestinal dysmotility. For example, _. Q - Table 1 reports the results of five separate studies, three in- patient and two outpatient, on the same patient at the research hospital. The first study was of two days .duration. The lengths of subsequent studies are as indicated. The reports Tables 1 to 5 are for patients with chronic constipation. Those in Tables 6, 7 and 8 are for patients with irritable bowel syndrome. Tables 9 and 10 are summaries. TABLE 1 Patient Number 1 A.O., a 53 year old female f R t ooue H - d A ii smn¬ itt orna d Sty u i A t cv ϋl 1 P 452 41 1.8 No change (lnpat- ient) 2 A 29.2 649 52 3.0 Marked improvement n p.o. 1 A 21.6 985 77 4.7 Marked improvement (inpat- lent) 2 A 21.6 997 77 3.3 Marked Improvement 3 A 21.6 806 65 2.4 Marked improvement #3 p.o. 1 A 21.6 Average day (outpat¬ ient) 2 A 21.6 Better than average day 3 A 21.6 lF ' eca Much better than average day 4 P Average day St som y m p , i S s g n, Ct senomm H- ✓-> re o re i- * - •*■ * - a c σ d Study rt rt rt TJ • - » *β •»— s {s a JJ, rt rt I I Route of Adminis¬ tration Study Ui OJ S3 OJ r Day d Active (0 H a ¬ Compound TJ rt or Placebo ft * i NJ IS3 to S3 to Total 24 1 1 y y » • y • • VO r Hour Dose <y> c N3 S3 (mg) Fecal • On S3 y Fat (%) Symptoms, Signs, Comments -61- . ε TABLE 2 Patient Number 2 B.K., a 30 year old female 2 A 21.6 125 66 5.9 3 A 21.6 230 82 9.0 4 A 7.2 34 12 0.8 5 P 0 No β ool 6 P 0 43 • 7 0.9 7 P 0 No stool TABLE 3 Patient Number 3 J.P., a 39 year old male o >ϊ .q m 1 cd •d α> f CO O o co d P d ϋ CM O •μ •H o α> d d ft 4 4-1 6-S d <u d > H > O PC H v -a 4-1 -H -M T) •H cd <— » cd d d a d 4-1 g. H* y cd u cd •u d ϋ - ϋ 4-» ■P ϋ -, O O O <u OJ O 4 - CΛ O H W a to s. 01 u (U cd to O v β_>, to to u o #1 i.v. 1 A 29.2 No stool 2 P No stool 3 No stool I 4 No stool t y i 5 No stool n p.o , 1 No stool 2 No stool 3 No stool 4 No stool 5 21.6 No stool [ Sts om y m p 1i S s g n, Study Route of Adminis¬ tration y o O 00 σv Study Day Active Compound Tl ι-ύ or Placebo t t Total 24 y y Hour Dose σ * σv (mg) Fecal Fecal ft o Dry Wt. d rt (gm) g ro CL Fecal Fat CO Symptoms, Signs, Comments -Z3- εεεoo/εssn/xDd z.6iεo/ε8 OΛV Sdty u TABLE 4 Patient Number 7 B.B., a 65 year old female f R t eoou A dii smn¬ itt oran CO CO o a •P « d ■ H P to α) cd (X d | υ P d it evc H bθ OJ t B c o A cd o dC o p onmu to to O bPl eorcoa H (In- i.v. 1 A 29.2 166 59 Cramps; improvement patient) Spontaneous passage of stool 2 P _ 205 42 Average; digital removal of stoo ϋ2 (in- p.o. 1 A 42l Tt ao 21.6 - missing No stool patient) DH ersouo 2 A 21. () 6 g m 238 35 Improvement;"natural easy BM'β 3 A 21.6 262 l F eac 35 Marked improvement;spontaneous WW tt e "natural BM's" )( m g 21.6 145 20 Marked improvement;spontaneous "natural BM's" l F eca 265 WD t yr 23 Marked Improvement;spontaneous )( m g "natural BM's" 299 36 Marked improvement;spontaneous "natural BM's" 166 38 Less improvement;less BM;still ■ spontaneous •d »a= Study y .—> ro y d d rt I Route of Adminis¬ tration Active Compound Hr} or Placebo to y ι- » "d Symptoms, ts α> Signs, m Comments w S -ΪZ-. εεεoo/ε8SΩ/.ιθd L6l£ /£S O TABLE 5 Patient Number 8 H.D., a 71 year old male #1 i.v. 1 P 144 12 I t- 2 A 29.2 281 17 Marked improvement I #2 p. o, 1 A 21.6 135 7 Marked improvement 2 A 21.6 134 14 Marked improvement 3 A 21.6 476 29 Marked improvement 4 P Spontaneous BM; but feces lost by patient because of sudden urge to pass BM 5 554 26 Improvement ■ **** & p N» rt rt . Study l- , -. ro o ro H> d c 3 d rt rt rt I Route of ■ o Adminis¬ tration * σv o Fecal • • o OJ Fat ( ) Symptoms, Signs, Comments εεεoo/εssn/xod ω Study . rt I Route of o Adminis¬ tration Study oo σ> Ui US to σv Day Active Compound or h-i Hti *τi Hti H\, *X> Placebo Total 24 to t y Hour Dose y I-* ■σ σv (mg) Fecal o Dry Wt. o p rt (gm) p. a c K. Fecal Fat U) Symptoms, Signs, Comments TABLE 6 (continued) o ■ft ω cp na 3 • -d- tn CO to o d 3 u M o o 3 d 3 (=3 P f- * ! O * 3 3 3 •rt . θ H r-l H 3- c * r-l "v^ to ω ■P -rt •P •3 •H PJ P 3 u /~\ 3 13 H ± 3 r-r. 3 3 » 3 3 P U υ ■ , a ϋ -P & A § u ■ a P a ω a P δ p o o d ω 3 3 o CO rt U •P •=! 3 3 p 3 3 p^ vi CO β J o o H W β. 1 . ^ « '~' . fe -4 to O o A 21.6 Good BM; no pain; marked improvement 10 A 10.8 Good BM; no pain; marked Improvement '11 A 18.0 Good BM; some pain; some gas 04 (out¬ p.o. 1 A 7.2 Pain; distention; average day patient) t 2 A 18.0 Pain; distention; average day o 3 A 21.6 Pain; spontaneous BM; slight improvement 4 A 18.0 Pain; distention; some improvement 5 A 21.6 No pain; minimal distention; marked improvement No pain; some distention; some improvement Distention; recurrent pain .Study Route of .Adminis¬ tration Study vo CO Day Active Compound Hti H ti or Placebo Total 24 .Hour Dose (mg) .Fecal Fecal ro o Dry Wt. P rt (gm) y g ro α. Fecal Fat (X) Symptoms , Signs, Comments εεεoo/εδsn/xDd TABLE 7 Patient Number 5 J.B. , a 19 year old female #1 (in- l.v. 29.2 61 14 2.6 Less distention; better than patient) average day 648 204 5.7 Less distention; better than average day if 2 (out¬ p.o. 1 A 10.8 253 75 0.8 Less distention patient) 2 A 21.6 Marked improvement; spontaneous BM 3 A 21.6 Spontaneous BM; some distention 4 P Distention; pain; cramps; marked deterioration 5 P Spontaneous BM; some pain; distent 6 P Distention; spontaneous BM Route of •3 Adminis¬ o tration .Study σv O to Day Active Compound or Placebo 24 ose eca Fat (%) Symptoms, Signs, Comments εεεoo/εssn/xDd TABLE 8 Patient Number 6 n (in- l.v. 1 A 29.2 No BM; marked Improvement with de¬ patient) creased pain and distention 2 P 21 ' 4 1.6 BM small; decreased pain and l distention t i n (out¬ 1 A 18.0 60 14 2.1. Spontaneous BM; no distention; patient) marked Improvement 2 A 21.6 44 6 2.3 Spontaneous BM; no distention; marked improvement 3 A 21.6 No BM; no pain or distention 4 A 21.6 Spontaneous BM; no symptoms 5 A 21.6 No stool; no symptoms 6 A/P .3.6 Spontaneous BM; no symptoms 7 P - No stool; average day ( • O'c ττ^) S3τpn3g * }U3χ3 * Bd: CM o O trt o X3S to to to aSy ' co σv σv r- o oo o αsqrnn^ CM CO 00 Λ OMPI ft ta Patient Initials co σv υt .&- Patient Number σv σv σv o CO Age • i Sex Outcome εεεoo/εssn/xod The following formulations illustrate procedures which can be employed to produce a variety of dosage forms of the active ingredients of this invention. The active ingredient in each formulation is naloxone. It could be naltrexone, nalmefene or any of the other compounds of this invention. TABLET Mg Tablet 1) Oral form: Naloxone hydrochloride 12 Starch 50 Lactose 75 Magnesium stearate 2 Stearic acid 5 The compound, a portion of the starch and the lactose are combined and wet granulated with starch paste. The wet granula- tion is placed on trays and allowed to dry overnight at a tempera¬ ture of 45° C. The dried granulation is comminuted in a comminutor to a particle size of approximately 20 mesh. Magnesium stearate, stearic acid, and the. balance of the starch are added and the entire mix blended prior to compression on a suitable tablet press. The tablets are compressed at a weight of 232 mg using a 11/12" punch with a balance of 4 kg. These tablets will disin¬ tegrate within a half hour according to the method described in SP -XVI. ' Mg Tablet 2) Naloxone 6 Microcrystalline cellulose 30 Spray-dried lactose 60 Colloidal silica 1 Stearic acid 1 Screen the alkaloid to break up lumps and blend with microcryεtalline cellulose. " Add spray-dried lactose and blend. Finally add the stearic acid and colloidal silica; blend to ob¬ tain homogenous mixture. Compress using 9/32 in shallow concave punch. CAPSULES 1) Naloxone hydrochloride 10 mg Lactose 45 Starch 45 The compound, a portion of the starch and the lactose are combined and wet granulated with starch paste. The wet granula¬ tion is placed on trays and allowed to dry overnight at a tem¬ perature of 45°C. The dried granulation is added to a hand gelatin capsule of the appropriate size. 2) Naloxone 20 mg Sesame oil 90 The free base is mixed with sesame oil and encapsulated in a soft gelatin capsule of the appropriate size. SUSTAINED RELEASE 1) Oral Naloxone (12 mg) is included in a Hydrophilic polymer matrix from which it will be gradually excluded following inges- tion. The inclusion is accomplished by dissolving the free base in a suitable non-polar solvent from which it will be absorbed by the polymers. Removal of the solvent leaves the product bound in the matrix from which it is released by water solution. Rates of delivery can be controlled by the ' hydrophilic character of the matrix which can be both non- or biodegradable as desired. 2) Oral Naloxone (12mg) is mixed with sucrose and compounded into 1 mm diameter pellets to yield a total of 200 pellets. Fifty beads are used in the uncoated form. The remaining beads are divided into three equal parts and coated with stearic acid, palmitic acid and glycerol myristate in appropriate amounts to allow dissolution in the intestine over 4, 8 or 12 hours. The beads are encapsulated in an appropriate size hard gelatin capsule. PARENTERAL Mg/cc 1) Naloxone hydrochloride 10 Methyl paraben 1.8 Propyl paraben 0.2 Water for injection q.s. The solution is prepared by first dissolving the parabens in hot water for injection, cooling to room temperature and dis¬ solving the compound and sodium chloride. It is then filtered, using sterile technique, through a bacteriological filter (0.6 micron or smaller porosity), after which it is transferred into ampoules or multiple-dose vials. 2) Naloxone 10 or 20 Ethanol 100 Propylene-glycol 880 The solution is prepared by dissolving the naloxone in the alcohol and diluting with propyl ene glycol. It is . then filtered using sterile techniques, through a bacteriological filter after which it is transferred into ampules or multiple dose vials. SUSTAINED RELEASE 1) Parenteral The hydrochloride salt of naloxone (20mg) is dissolved in an appropriate amount of ethanol. The solution is mixed with sesame oil (5:1 ratio) and heated at 45° under vacuum to remove the alcohol. The residue (drug in sesame oil) is transferred into individual or repeated dose ampoules. 2) Suppository Percent Naloxone hydrochloride 4.06 Polyoxyethylene 1000 (approx M 1000) ' 80.14 Polyαxyethylene 4000 (approx M 4000) 15.00 Methyl paraben .45 Propyl paraben .05 Purified water USP 3.10 The HCI salt of the compound is dissolved in the water and added to a melted mixture of the polyoxyethylenes which are al¬ ready combined with the parabens. This molten mixture is poured into suppository molds and cast into suppositories weighing 3 grams each. They are frozen to solidify and packaged into foil. 3) Tablet A total of 65 gm 15Z. hydrated propyl hydroxymethyl cellulose and 24 gm polyethylene oxide (mw= 5,000,000) are mixed O PI ^.^— -~~" * - ' ^ - " ' " _39_ - ' together with 10 gm of naloxone hydrochloride.in a uniform powdery slurry and 1 mg magnesium stearate is added. The mix is pressed into tablets at a pressure of 100 at . Each of the tablets contains 10 mg naloxone. A tablet when * orally administered 5 delivers the naloxone over a .period of 12 hours. 4) Tablet Nalmefene tablets which are suitable for a sustained release delivery over 12 hour periods are prepared by mixing in the conventional manner 63 gm 15% hydrated propyl hydroxy- 10 methyl cellulose and 24 gm polyethylene oxide (mw= 5,000,000) together with 12 gm of nalmefene hydrochloride in a uniform powdery slurry. The mix is pressed into tablets at a pressure of 100 atm, each of the tablets containing 12 mg nalmefene.

Claims: WHA IS CLAIMED:IS: 1. A method for the.restoration of normal motility in a patient afflicted with an intestinal dysmotility which comprises the administration of an amount which is effective to restore motility of a compound represented by the formula: wherein 3 is 3 , -methyl-2-buteneyl; allyl; cyclopropylmethyl; or cyclobutylmethyl and pharmaceutically acceptable salts thereof. 2. A method as in claim 1 wherein the method of administra¬ tion is oral and the amount administered is from about 10 to about 50 mg per day. 3. A method as in claim 1 wherein the method of administra¬ tion is parenteral and the amount administered is from about 10 to about 70 mg per day. 4. A method as in claim 1, 2 or 3 wherein the compound administered is naloxone. 5. A method as in claims 1, 2 or 3 wherein the compound administered is naltrexone. 6. A method as in claims 1, 2 or 3 where the result of the dismotility is constipation. 7. A method as in claims 1, 2 or 3 wherein-the .result of the dysmotility is irritable bowel syndrome. " 8. A method as.in claims 1, 2 or 3 wherein the result of the dysmotility is constipation, and the compound .administered is naloxone. 9. A method as in claims 1, 2 or 3 wherein the result of the dy.smotility is constipation, and the compound administered is naltrexone. 10. A method as in claims 1, 2 or 3 wherein the result of the dysmotility is irritable bowel syndrome and the compound adminis¬ tered is naloxone. 11. A method as in claims 1, 2 or 3 wherein the result of the dysmotility is irritable bowel syndrome and the compound administered is naltrexone. 12. a method for the restoration of normal motility in a patient afflicted with intestinal dysmotility which comprises administration of an amount which is effective to restore normal motility of a compound represented by the formula: Otøpj ~ ' . -~ Ϊ — " ~ - - -- - " _ 4 2 - " - " wherein R is allyl or cyclopropylmethyl, R-^ is hydrogen or hydroxy and Rr, is hydroxy or .methoxy and pharmaceutically acceptable salts thereof . 13. A method as in claim 12 wherein - the method of administra- tion is oral and the amount administered is from about 10 to 50 mg per day. 14. A method as in claim 12 wherein the method of administra¬ tion is oral and the amount administered is from about 10 to 70 mg per day. 15. A method as in claims 12, 13 or 14 wherein the compound administered is nalmefene. 16. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is constipation. 17. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is irritable bowel syndrome. 18. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is constipation, and the compound administered is nalmefene. 19. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is irritable bowel syndrome and the compound administered is nalmefene. 20. A method for the restoration of normal motility in a patient afflicted with intestinal dysmotility which comprises administration of an amount which is effective to restore motility of a compound represented by the formula: and the corresponding dehydro compounds wherein R^is methoxy or hydroxy, R5 is hydrogen or hydroxy, and Rg is hydrogen, methyl, ethyl, propyl, allyl and benzyl, and the parmaceutically acceptable salts thereof. 21. A method as in claim 20 wherein the method of adminis¬ tration is oral and the amount administered is from about 10 to about 50 mg per day. 22. A method as in claim 20 wherein the method of administra¬ tion is parenteral and the amount administered is from about 10 to about 70 mg per day. 23. A method as in claims 20, 21 or 22 wherein the result of the dysmotility is constipation. 24. A method as in claims 20, 21 or 22 wherein the result of the dysmotility is irritable bowel syndrome. UM 25. A sustained .release formulation suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal utility, the antagonist being represented by the formula: wherein 3 is 3'-methyl-2-butenyl; allyl; cyclopropylmethyl; or cyclobutylmethyl and including the pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, from about 5% to 20% of opioid antagonist and from 80% to 95% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at least one of them is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. 26. A formulation as in Claim 25 wherein the opioid antagon¬ ist is naloxone. 27. A formulation as in Claim 25 wherein the opioid antagon¬ ist is naltrexone. 28. A formulation as in Claim 25, 26 or 27 wherein the hydrated alkyl hydroxy cellulose is propyl hydroxyπethyl cellulose. 29. A formulation as in Claim 25, 26, 27 or 28 in dosage unit form. 30. A sustained release formulation suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal utility, the antagonist being represented by the formula: wherein R is allyl or cyclopropylmethyl, j _ is hydrogen or hydroxy and 2 is hydroxy or methoxy and including the pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, from about 5% to 20% of opioid antagonist and from 80% to 95% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at lease one of they is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. 31. A formulation as in Claim 30 wherein the opioid antagonist is nalmefene. 32. A formulation as in Claim 30 wherein-the hydrated alkyl hydroxy cellulose is propyl hydroxymethyl cellulose. 33. A formulation as in Claim 30, 31 or 32 in dosage unit form. 34. A sustained-release formulation suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal utility, the antagonist being represented by the formula: and the corresponding dehydro compounds wherein R4 is methoxy or hydroxy, R5 is hydrogen or hydroxy, and Rg is hydrogen, methyl, ethyl, propyl, allyl and benzyl, and including pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, from about 5% to 20% of opioid antagonist and from 80% to 85% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at least one of them is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. 35. A formulation as in Claim 34 wherein the hydrated alkyl hydroxy cellulose is propyl hydroxymethyl cellulose. 36. A formulation as in claim 34 or 35 in dosage unit form. 37. A method for the restoration of normal motility in a patient afflicted with an intestinal dysmotility which is independent of prior administration of opioid agonists which comprises the administration of an amount of pure opioid antagonist which is effective to restore motility. 38. A sustained release formulation suitable for administering an opioid antagonist to a patient to restore normal intestinal motility comprising from 5% to 20% of -an opioid antagonist and from 80% to 95% of a carrier, said carrier c πprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups con¬ tain up to four carbon atoms and at least one of them is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharma- ceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being frcm 5% to 25% by weight based on its total weight. AME DED CLAIMS (received by the International Bureau on 09 August 1983 (09.08.83)) 1. A method for the restoration of normal motility in a patient afflicted with an intestinal dysmotility which ' is independent of prior administration of opioid agonists which -comprises the administration of an amount which is effective to restore motility of a compound represent by the formula: wherein R3 is 3*-methyl-2-buteneyl; allyl; cyclopropylmethyl; or cyclobutylmethyl and pharmaceutically acceptable salts thereof. 2. A method as in claim 1 wherein the method of administra¬ tion is oral and the amount administered is from about 10 to about 50 mg per day. 3. A method as in claim 1 wherein the method of administra¬ tion is parenteral and the amount administered is from about 10 to about 70 mg per day. 4. A method as in claim 1, 2 or 3 wherein the compound administered is naloxone. 5. A method as in claims 1, 2 or 3 wherein the compound administered is naltrexone. 6. A method as in claims 1, 2 or 3 where the result of the dismotility is constipation. -49- 7. A method as in claims 1, 2 or 3 wherein.the result of the - dysmotility is irritable bowel syndrome. 8. A method as.in claims 1, 2 or 3 wherein the.result of the dysmotility is constipation, and the compound administered is naloxone. 9. A method as in claims 1, 2 or 3 wherein the result of the -dysmotility is constipation, and the compound administered is naltrexone. 10. A method as in claims 1, 2 or 3 wherein the result of the dysmotility is irritable bowel syndrome and the compound adminis¬ tered is naloxone. 11. A method as in claims 1, 2 or 3 wherein the result of the dysmotility is irritable bowel syndrome and the compound administered is naltrexone. 12. A method for the restoration of normal motility in a patient afflicted with intestinal dysmotility which is independent of prior ad¬ ministration of opioid agonists which c nprises administration of an amount which is effective to restore normal motility of a ccπpound repr sented by. the formula: -50- wherein R is allyl or cyclopropylmethyl, .^ is hydrogen or hydroxy and « is hydroxy or .methoxy and pharmaceutically acceptable salts thereof. 13. A method as in claim 12 wherei -the method of administra- tion is oral and the amount administered is from about 10 to 50 mg per day. 14. A method as in claim 12 wherein the method of administra¬ tion is oral and the amount administered is from about 10 to 70 mg per day. 15. A method as in claims 12, 13 or 14 wherein the compound administered is nalmefene. 16. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is constipation. 17. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is irritable bowel syndrome. 18. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is constipation, and the compound administered is nalmef ne. 19. A method as in claims 12, 13 or 14 wherein the result of the dysmotility is irritable bowel syndrome and the compound administered is nalmefene. 20. A method for the restoration of normal motility in a patien ' t afflicted.with intestinal dysmotility which is independent of- prior administration of opioid agonists which comprises administration o an amount which is effective to restore irotility of a compound repre- sented by the formula: -51- 25. A sustained release formulation suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal πptility, the antagonist being represented by the formula: wherein 3 is 3 '-methyl-2-butenyl; allyl; cyclopropylmethyl; or cyclobutylmethyl and including the pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, from about 5% to 20% of opioid antagonist and from 80% to 95% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at least one of them is propyl or butyl, and, based on the total weight, from. 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. ' 2-6. A formulation as in claim 25 wherein the opioid antagon¬ ist is naloxone. 27. A formulation as in Claim 25 wherein the opioid antagon¬ ist is naltrexone. 28. A formulation as in Claim 25, 26 or 27 wherein the hydrated alkyl hydroxy cellulose is propyl hydroxyπethyl cellulose. 'BUREA -52- 29. A formulation as in Claim 25, 26, 27 or 28 in dosage unit form. 30. A sustained release formulation ' suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal motility, the antagonist being represented by the formula: wherein R. is allyl or cyclopropylmethyl, ] _ is hydrogen or hydroxy and R 2 is hydroxy or methoxy and including the pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, from about 5% to 20% of opioid antagonist and from 80% to 95% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at lease one of they is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. 31. A formulation as in Claim 30 wherein the opioid antagonist is nalmefene. O P 32. A formulation as in Claim 30 wherein the hydrated alkyl hydroxy cellulose is propyl hydroxymethyl cellulose. 33. A formulation as in Claim 30, 31 or * 32 in dosage unit form. 34. A sustained release formulation suitable for administer¬ ing an opioid antagonist to a patient to restore normal intestinal iϊDtϋity, the antagonist being represented by the formula: and the corresponding dehydro compounds wherein R is methoxy or hydroxy, R5 is hydrogen or hydroxy, and Rg is hydrogen, methyl, ethyl, propyl, allyl and benzyl, and including pharmaceutically acceptable salts thereof; said formulation containing, based on the total weight, rom about 5% to 20% of opioid antagonist and from 80% to 85% of a carrier, said carrier comprising a release agent together with from, based on the total weight, 70% to 30% of_- a hydrated alkyl hydroxy cellulose in which the alkyl groups contain up to four carbon atoms and at least one of them is propyl or butyl, and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydroxy cellulose being from 5% to 25% by weight based on its total weight. * 35. A formulation ' as in Claim 34 wherein the hydrated alkyl hydroxy cellulose is propyl hydroxymethyl cellulose. 36. ' A formulation as in claim 34 or 35 in dosage unit form. 37. A method for the restoration of normal motility in a patient afflicted with an intestinal dysmotility which is independent of prior administration of opioid agonists which comprises the administration of an amount of pure opioid antagonistwhich is effective to restore motility 38. A sustained release formulation suitable for administration o a pure opioid antagonist to a patient to restore normal intestinal motili said formulation containing, based on the total weight, from 5% to 20% of pure opioid antagonist and from 80% to 95% of a carrier, said carrier cαrt prising a release agent together with from, based on the total weight, 70 to 30% of a hydrated alkyl hydroxy cellulose in which the alkyl groups co tain up to four carbon atαns and at least one of them is propyl or butyl, ■and, based on the total weight, from 30% to 70% of a pharmaceutically acceptable polyalkylene oxide, the degree of hydration of the alkyl hydrox cellulose being from 5% to 25% by weight based on its total weight. 39. A formulation as in Claim37wherein the hydrated alkyl hydro cellulose is propyl hydroxymethyl cellulose. -40. A formulation as in Claim38 or39 in dosage unit form. STATEMENTUNDERARTICLE 19 New pages 40 to 42 and 44 to 47 replace the same numbered pages in the application presently on file. The new pages are for the purpose of making the following changes in the claims: Claims 1, 12 and 20: at line 2, in each instance insert "which is independent of prior administration of opioid agonists" after "dysmotility". Claim 12, line 1: change "a" to "A". Claims 25, 30 and 34: at line 3, in each instance change "utility" to read "motility". Claim 38, lines 1 and 2: change "administering an" to "administration of a pure". Claim 38, line 3: change "comprising" to "; said formulation containing, based on the total weight,". Claim 38, line 3: change "an" to "pure". Page 47 introduces new claims 39 and 40.

Inventors: FISHMAN JACK, KREEK MARY JEANNE, FISHMAN, JACK, KREEK, MARY, JEANNE
Applicants: UNIV ROCKEFELLER, THE ROCKEFELLER UNIVERSITY
Application year: 1983
Main classification: A61K9
IPC codes: A61K9, A61K31, C07D307, C07D489