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`APPLICATION NUMBER:60/123,244
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`FILING DATE:March 08, 1999
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`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
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`This is a requestfor filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (C).
`
`Given Name(first and middle[if any))
`Elizabeth
`Joanne
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`INVENTOR(S)
`Family Name or Sumame
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`Stoner
`Waldstreicher
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`Scatch Plains, New Jersey
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`[[] Additional inventors are being named on the__ separately numbered sheets attached hereto
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`TITLE OF THE INVENTION (280 characters max)
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`METHODS AND COMPOSITONS FOR TREATING ERECTILE DYSFUNCTION
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`CORRESPONDENCE ADDRESS
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`Merck & Go., Ine.
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`TITLE OF THE INVENTION
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`METHODS AND COMPOSITIONS FOR TREATING ERECTILE
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`DYSFUNCTION
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`FIELD OF THE INVENTION
`The present invention provides for novel methods for the
`treatment of erectile dysfunction comprising a drug combination. More
`particularly, the drug combination of the present invention comprises
`an agonist of the melanocortin receptor with a cyclic-GMP-specific
`phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist.
`The present invention also provides for pharmaceutical compositions
`comprising such drug combinations useful in the methods to treat
`erectile dysfunction. Moreover, the present invention provides for a
`method of manufacture of a medicament useful in the treatment of
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`BACKGROUND OF THE INVENTION
`Erectile dysfunction denotes the medical condition of
`inability to achieve penile erection sufficient for successful sexual
`intercourse. The term “impotence” is oftentimes employed to describe
`this prevalent condition. Approximately 140 million men worldwide,
`and, according to a National Institutes of Health study, about 30 million
`American men suffer from impotencyor erectile dysfunction. It has
`been estimated that the latter number could rise to 47 million men by the
`year 2000. Erectile dysfunction can arise from either organic or
`psychogenic causes, with about 20% of such cases being purely
`psychogenic in origin. Erectile dysfunction increases from 40% at age
`40, to 67% at age 75, with over 75% occurring in men over the age of 50.
`In spite of the frequent occurrence of this condition, only a small
`number of patients have received treatment because existing treatment
`alternatives, such as injection therapies, penile prosthesis implantation,
`and vacuum pumps, have been uniformly disagreeable [for a discussion,
`see “ABC of sexual health - erectile dysfunction,”Brit.Med.J.318: 387-
`390 (1999)}. Only more recently have more viable treatment modalities
`become available, in particular orally active agents, such as sildenafil
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`citrate, marketed by Pfizer under the brand name of Viagra®. Sildenafil
`is a selective inhibitor of type V phosphodiesterase (PDE-V), a cyclic-
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`GMP-specific phosphodiesterase isozyme [see R.B. Moreland etal.,
`“Sildenafil: A Novel Inhibitor of Phosphodiesterase Type 5 in Human
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`Corpus Cavernosum Smooth Muscle Cells,” Life Sci., 62: 309-318 (1998)].
`Prior to the introduction of Viagra on the market, less than 10% of
`patients suffering from erectile dysfunction received treatment.
`Sildenafil is also being evaluated in the clinic for the treatment of female
`sexual dysfunction.
`The regulatory approval of Viagra® for the oral treatment of
`erectile dysfunction has invigorated efforts to discover even more
`effective methods to treat erectile dysfunction. Several additional
`selective PDE-V inhibitors are in clinical trials. UK-114542 is a sildenafil
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`IC-351 (ICOS
`backup from Pfizer with supposedly improved properties.
`Corp.) is claimed to have greater selectivity for PDE-V over PDE-VI than
`sildenafil. Other PDE-V inhibitors include M-54033 and M-54018 from
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`Mochida Pharmaceutical Co. and E-4010 from Eisai Co., Ltd.
`Other pharmacological approaches to the treatment of
`erectile dysfunction have been described [see, e.g., “Latest Findings on
`the Diagnosis and Treatment of Erectile Dysfunction,” Drug News &
`Perspectives, 9: 572-575 (1996); “Oral Pharmacotherapyin Erectile
`Dysfunction,” Current Opinion in Urology, 7: 349-353 (1997)]. A product
`under clinical development by Zonagen is an oral formulation of the
`alpha-adrenoceptor antagonist phentolamine mesylate under the brand
`name of Vasomax®. Vasomax® is also being evaluated for the
`treatment of female sexual dysfunction.
`Drugs to treat erectile dysfunction act either peripherally or
`centrally. They are also classified according to whether they “initiate” a
`sexual responseor “facilitate” a sexual response to prior stimulation [for
`a discussion, see “A Therapeutic Taxonomy of Treatments for Erectile
`Dysfunction: An Evolutionary Imperative,” Int. J. Impotence Res., 9:
`115-121 (1997)}. While sildenafil and phentolamine act peripherally and
`are considered to be “enhancers”or “facilitators” of the sexual response
`to erotic stimulation, sildenafil appears to be efficacious in both mild
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`organic and psychogenicerectile dysfunction. Sildenafil has an onset of
`action of 30-60 minutes after an oral dose with theeffect lasting about 4
`hours, whereas phentolamine requires 5-30 minutes for onset with a
`duration of 2 hours. Although sildenafil is effective in a majority of
`patients, it takes a relatively long time for the compoundto show the
`desired effects. The faster-acting phentolamine appearsto be less
`effective and to have a shorter duration of action than sildenafil. Oral
`sildenafil is effective in about 70% of men who take it, whereas an
`adequate response with phentolamine is observed in only 35-40% of
`patients. Both compoundsrequire erotic stimulation for efficacy. Since
`sildenafil indirectly increases blood flow in the systemic circulation by
`enhancing the smooth muscle relaxation effects of nitric oxide, it is
`contraindicated for patients with unstable heart conditions or
`cardiovascular disease, in particular patients taking nitrates, such as
`nitroglycerin, to treat angina. Other adverse effects associated with the
`clinical use of sildenafil include headache, flushing, dyspepsia, and
`“abnormalvision,” the latter the result of inhibition of the type VI
`phosphodiesterase isozyme (PDE-VI), a cyclic-GMP-specific
`phosphodiesterase that is concentrated in the retina. “Abnormal vision”
`is defined as a mild andtransient “bluish” tinge to vision, but also an
`increased sensitivity to light or blurred vision. Moreover, since some
`patients have developed a tolerance to prior phosphodiesterase
`inhibitors, sildenafil may prove to have a similar outcome in some
`percentage of patients when used over a long period of time.
`Synthetic melanocortin receptor agonists (melanotropic
`peptides) have been foundto initiate erections in men with psychogenic
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`erectile dysfunction [See H. Wessells et al., “Synthetic Melanotropic
`Peptide Initiates Erections in Men With Psychogenic Erectile
`Dysfunction: Double-Blind, Placebo Controlled Crossover Study,” J.
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`Urol., 160: 389-393 (1998); Fifteenth American Peptide Symposium, June
`14-19, 1997 (Nashville TN)]. Activation of melanocortin receptors of the
`brain appears to cause normal stimulation of sexual arousal. In the
`above study, the centrally acting a-melanocyte-stimulating hormone
`analog, melanotan-IJ (MT-I]), exhibited a 75% responserate, similar to
`results obtained with apomorphine, when injected intramuscularly or
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`subcutaneously to males with psychogenic erectile dysfunction. MT-II
`is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-
`NHg9,which contains the 4-10 melanocortin receptor binding region
`common to o-MSH and adrenocorticotropin, but with a lactam bridge.
`MT-II (also referred to as PT-14) (Erectide®) is presently in clinical
`development by Palatin Technologies, Inc. and TheraTech, Inc. as a
`non-penile subcutaneous injection formulation. An oral transmucosal
`delivery system for the drug is also being developed. It is considered to
`be an “initiator” of the sexual response. The time to onset of erection
`with this drug is relatively short (10-20 minutes) with a duration of
`action approximately 2.5 hours. Adverse reactions observed with MT-II
`include nausea, flushing, loss of appetite, stretching, and yawning.
`Adverse effects associated with MT-II may be the result of
`the lack of selectivity of the compound for a particular melanocortin
`receptor subtype. To date, five melanocortin receptor subtypes have been
`cloned. Evidence has been presented suggesting that the erectogenic
`properties of melanocortin agonists are mediated via binding to the MC-
`4R subtype. Whereas MC-3Ris expressed in the brain, gut, and
`placenta, the MC-4R subtype is uniquely expressed in the brain, and
`inactivation has been found to cause obesity.
`Because of the unresolved deficiencies of the various
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`pharmacological agents discussed above, there is a continuing need in
`the medical arts for improved methods and compositions to treat
`individuals suffering from psychogenic and/or organic erectile
`dysfunction. Such methods should have wider applicability, enhanced
`convenience and ease of compliance, short onset of action, reasonably
`long duration of action, and minimal side effects with few
`contraindications, as compared to agents now available.
`It is therefore an object of the present invention to provide
`methodsof treating erectile dysfunction which comprise the
`administration to a human subject in need thereof a centrally-acting
`agent that “initiates” an erectogenic response in combination with
`another centrally-acting agent or a peripherally-acting agent that
`“facilitates” or “enhances” the response to erotic stimulation. The
`human subject may be either male or female.
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`It is another object of the present invention to provide
`pharmaceutical compositions comprising the combination that are
`useful in the methods of the present invention.
`It is still a further object of the present invention to provide a
`method of manufacture of a medicament useful in the treatmentof
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`erectile dysfunction.
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`SUMMARY OF THE INVENTION
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`The present invention provides for methodsof treating
`erectile dysfunction in a human subject in need of such treatment
`comprising administration of a therapeutically effective amount of an
`agonist of the melanocortin receptor in combination with a
`therapeutically effective amountof a cyclic-GMP-specific
`phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist.
`Further, the present invention provides for pharmaceutical
`compositions useful in the methods of the present invention, as well asa
`method of manufacture of a medicament useful to treat erectile
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`dysfunction.
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`DETAILED DESCRIPTION OF THE INVENTION
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`The present invention is concerned with the combination of
`an agonist of the melanocortin receptor with a cyclic-GMP-specific
`phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist
`for the treatment of erectile dysfunction in a male or female human
`subject. This particular combination produces unexpectedly superior
`pharmacokinetic and pharmacodynamic results in the treatment of
`male or female erectile dysfunction. Thus, it is an object of the instant
`invention to describe the combination of the two drugs in the treatment of
`erectile dysfunction. In addition, it is an object of the instant invention to
`describe preferred embodiments within each category of compounds
`which are used as elements in the instant combination. It is a further
`object of this invention to describe compositions containing each of the
`compoundsfor use in the treatment of erectile dysfunction. It is a still
`further object of this invention to describe a method of manufacture of a
`medicament containing the present drug combination which is useful
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`for the treatment of erectile dysfunction. Further objects will become
`apparent from a reading of the following description.
`The instant combination for the treatment of erectile
`dysfunction contains as a first element an agonist of the melanocortin
`receptor. Representative agonists of the melanocortin receptor are
`disclosed in the following publications, which are incorporated by
`reference herein in their entirety:
`
`(1) M. E. Hadley et al., “Discovery and Development of Novel
`Melanogenic Drugs,” in Integration of Pharmaceutical Discovery and
`
`Development: Case Studies, edited by Borchardt et.al., Plenum Press,
`New York, 1998;
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`(2) R.T. Dorr, etal., “Evaluation of Melanotan-II, A Superpotent Cyclic
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`Melanotropic Peptide in a Pilot Phase-I Clinical Study,” Life Sci., 58:
`1777-1784 (1996); and
`(8) R.A.H. Adan, “Identification of Antagonists for Melanocortin MC3,
`MC4, and MC5 Receptors,” European J. Pharmacol., 269: 331-337 (1994).
`Compositions and methods for the treatment of psychogenic
`erectile dysfunction comprising melanotropic peptides are disclosed in
`U.S. Patent No. 5,576,290 and CA 2,158,425, which are incorporated by
`reference herein in their entirety.
`In the instant combination for the treatment of erectile
`
`dysfunction, the first element of the combination is an agonist of the
`melanocortin receptor. In one embodiment of the combination of the
`present invention, the agonist of the melanocortin receptor is
`melanotan-JI (MT-II).
`In another embodiment of the combination of the present
`invention, the agonist of the melanocortin receptor is selective for the
`MC-4R subtype. Selective MC-4R agonists have been described, and
`reference is made to the following disclosures, which are incorporated
`by reference herein in their entirety:
`(1) C. Haskell-Luevano,et al., “Discovery of Prototype Peptidomimetic
`Agonists at the Human Melanocortin Receptors MCIR and MC4R,”
`J.Med. Chem., 40: 2133-2139 (1997); and
`(2) H.B. Schioth, et al., “Discovery of Novel Melanocortin-4 Receptor
`Selective MSH Analogues,” Brit. J. Pharmacol., 124: 75-82 (1998).
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`In the instant combination for the treatmentof erectile
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`dysfunction, the second element of the combination is composedofeither
`a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-
`adrenergic receptor antagonist.
`In a further embodimentof the
`combination of the present invention, the second element of the
`combination is a cyclic-GMP-specific phosphodiesterase inhibitor
`selective for the type V phosphodiesterase isozyme (PDE-V).
`Representative PDE-V inhibitors are disclosed in the patent and
`scientific literature. The Pfizer pyrazolo[4,3-d]pyrimidin-7-one PDE-V
`inhibitors are disclosed in WO 94/28902; WO 96/16644; WO 96/16657; EP
`0,702,555; EP 0,463,756; CA 2,163,446; and U.S. Patent No. 5,250,534; all of
`which are incorporated by reference herein in their entirety. Sildenafil
`is the generic namefor 1-[4-ethoxy-(6,7-dihydro-1-methyl-7-oxo-3-propyl-
`1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl-piperazine.
`For a discussion of its efficacy in the treatment of male erectile
`dysfunction, reference is made to J. Goldstein etal., N. Engl. J. Med.,
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`338: 1397-1404 (1998) and M.Boolell et al., “Sildenafil: an orally active type
`5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of
`penile erectile dysfunction,” Int. J. Impotence Res., 8: 47-52 (1996).
`The ICOSCorp. tetracyclic PDE-V inhibitors are disclosed
`in WO 95/19978; WO 97/03675; and WO 97/19978; all of which are
`incorporated by reference herein in their entirety. IC-351 represents
`(6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methy1-6-(3,4-
`methylenedioxyphenyl)-pyrazino[2’,V’: 6,1]pyrido[3,4-b]lindole-1,4-dione
`and is disclosed in WO 97/03675for the treatment of impotence.
`The Mochida Pharmaceutical Co. pyridocarbazole series of
`PDE-V inhibitors, of which M-54018 and M-54033 are members,is
`disclosed in WO 97/45427, which is incorporated by reference herein in
`its entirety. Other structural classes of PDE-V inhibitors are disclosed
`in WO 98/16224 (E. Merck GmbH), WO 99/02161 (Forssmann), WO
`98/07430 (Eisai), and JP 8225541 (Hisai), all of which are incorporated by
`reference herein in their entirety.
`In a class of this embodiment of the present invention, the
`combination for the treatmentof erectile dysfunction comprises an
`agonist of the melanocortin receptor and a PDE-V inhibitor selected from
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`the group consistingof sildenafil citrate, IC-351, M-54018, and M-54033.
`In a subclass of this class of the present invention, the agonist of the
`melanocortin receptor is MT-II. In another subclass of this class of the
`present invention, the combination of the present invention comprises a
`selective agonist of the melanocortin-4 receptor and a PDE-V inhibitor
`selected from the group consisting of sildenafil citrate, IC-851, M-54018,
`and M-54033. An especially preferred combination is a selective agonist
`of the melanocortin-4 receptor (MC-4R) andsildenafil citrate.
`In another embodiment of the combination of the present
`invention, the second element of the combination is an alpha-adrenergic
`receptor antagonist. In a class of this embodimentof the present
`invention, the alpha-adrenergic receptor antagonist is selective for the
`alpha-2 receptor subtype. In a subclassof this class of the present
`invention, the alpha-2 receptor antagonist is yohimbine or delquamine.
`The efficacy of yohimbine in the treatment of psychogenic erectile
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`dysfunction is reported in Lancet, pp. 42-43 (1987). Delquamineis an
`alpha adrenoreceptor antagonist, with a greater affinity for the alpha-2
`2 receptor subtype [see A. Moralesetal., “Oral and topical treatment of
`erectile dysfunction,” Urol. Clin. North Am., 22: 879-885 (1995)].
`In another subclassof this class of the present invention,
`the alpha-2 receptor antagonist is an arylquinolizine derivative disclosed
`in U.S. Patent Nos. 4,824,849 and 4,710,504, both of which are
`incorporated by reference herein in their entirety. In a subclass of this
`subclass of the present invention, the alpha-2 receptor antagonist is the
`benzofuroquinolizine analog, MK-912, disclosed in U.S. Patent No.
`4,824,849. MK-912 represents 1’,3’-dimethylspiro(1,3,4,5’,6,6’,7,12b-
`octahydro-2H-benzo[b]-furo[2,3-a]quinolizine)-2,4’-pyrimidin-2’-one and
`is a potent, orally active agent with a pharmacologic profile consistent
`with alpha-2 antagonism [see D.J. Pettibone, etal., “Pharmacological
`profile of a new potent and specific alpha2-adrenoceptor antagonist, L-
`657,743,” Naunyn-Schmiederberg’s Arch. Pharmacol., 336: 169-175
`(1987)]. The effect of the drug on penile erections in healthy male
`volunteers was observed by B.J. Gertz etal. and reported in Clin.
`Pharmacol. Ther., 46: 566-575 (1989). An especially preferred
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`combination is a selective agonist of the melanocortin-4 receptor (MC-4R)
`and MK-912.
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`The instant combination of an agonist of the melanocortin
`receptor and a cyclic-GMP-specific phosphodiesterase inhibitor or an
`alpha-adrenergic receptor antagonist is useful in the therapeutic
`treatmentof erectile dysfunction. Although the methods and
`compositions comprising drug combinations of the present invention are
`envisaged primarily for the treatment of male erectile dysfunction, they
`may also be useful for the treatment of female sexual dysfunction,
`including orgasmic dysfunction related to clitoral disturbances.
`The combination of an agonist of the melanocortin receptor
`and a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-
`adrenergic receptor antagonist provides an unexpectedly superior effect
`in the treatmentof erectile dysfunction. The combination provides for
`effective treatment of either psychogenic or organic erectile dysfunction
`in a greater percentageof the affected population than either element of
`the combination separately. The combination provides for a shorter
`onset of action and longer duration of action than either elementof the
`combination separately. The combination also has fewer side effects and
`contraindications than either memberof the combination separately.
`For use in medicine, the salts of the compoundsof this
`invention refer to non-toxic "pharmaceutically acceptable salts." Other
`salts may, however, be useful in the preparation of the compounds
`according to the invention or of their pharmaceutically acceptable salts.
`Salts encompassed within the term "pharmaceutically acceptable salts"
`refer to non-toxic salts of the compoundsof this invention which are
`generally prepared by reacting the free base with a suitable organic or
`inorganic acid. Representative salts include the following:
`Acetate, Benzenesulfonate, Benzoate, Bicarbonate,
`Bisulfate, Bitartrate, Borate, Bromide, Camsylate, Carbonate, Chloride,
`Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate,
`Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
`Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
`Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate,
`Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
`
`10
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`15
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`20
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`25
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`30
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`35
`
`-9-
`
`
`
`0011
`
`0011
`
`

`

`k
`
`20315PV
`
`
`
`fewat
`
`rial
`
`
`
`Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate,
`Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate
`(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
`Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate,
`Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
`Furthermore, where the compoundsof the invention carry an acidic
`moiety, suitable pharmaceutically acceptable salts thereof may include
`alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal
`salts, e.g., calcium or magnesium salts; and salts formed with suitable
`organic ligands, e.g., quaternary ammonium salts.
`The compounds of the present invention may have chiral
`centers and occur as racemates, racemic mixtures and as individual
`diastereomers, or enantiomers with all isomeric forms being included
`in the present invention. Therefore, where a compoundis chiral, the
`separate enantiomers, substantially free of the other, are included
`within the scope of the invention; further included are all mixtures of
`the two enantiomers. Also included within the scope of the invention are
`polymorphs and hydrates of the compoundsof the instant invention.
`The present invention includes within its scope prodrugs of
`the compoundsof this invention.
`In general, such prodrugswill be
`functional derivatives of the compoundsof this invention which are
`readily convertible in vivo into the required compound. Thus,in the
`methods of treatment of the present invention, the term "administering"
`shall encompass the treatment of erectile dysfunction with the
`compoundspecifically disclosed as an element of the combination or
`with a compound which may not be specifically disclosed, but which
`converts to the specified compoundin vivo after administration to the
`patient. Conventional procedures for the selection and preparation of
`suitable prodrug derivatives are described, for example, in "Design of
`Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of these
`compounds include active species produced upon introduction of
`compounds of this invention into the biological milieu.
`The term "therapeutically effective amount” shall mean
`that amount of a drug or pharmaceutical agent that will elicit the
`
`10
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`15
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`25
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`30
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`0012
`
`0012
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`

`

`20315PV
`
`
`
`
`BnHu
`
`biological or medical response of a tissue, system, animal or human that
`is being sought by a researcheror clinician.
`As used herein, the term “composition” is intended to
`encompass a product comprising the specified ingredients in the
`specified amounts, as well as any product which results, directly or
`indirectly, from combination of the specified ingredients in the specified
`amounts.
`
`In the combination of the present invention, the agonist of
`the melanocortin receptor may be administered separately or in
`conjunction with the cyclic-GMP-specific phosphodiesterase inhibitor or
`the alpha-adrenergic receptor antagonist. In addition, the
`administration of one element of the combination of the present
`invention maybe prior to, concurrent to, or subsequent to the
`administration of the other element of the combination.
`
`The elements of the combination of the present invention
`may be administered by oral, parenteral (e.g., intramuscular,
`intraperitoneal, intravenous or subcutaneous injection, or implant),
`buccal, nasal, vaginal, rectal, sublingual, or topical (e.g., ocular
`eyedrop) routes of administration and may be formulated, alone or
`together, in suitable dosage unit formulations containing conventional
`non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles
`appropriate for each route of administration.
`.
`The pharmaceutical compositions for the administration of
`the compounds of this invention may conveniently be presented in
`dosage unit form and may be prepared by any of the methods well known
`in the art of pharmacy. All methods include the step of bringing the
`active ingredient into association with the carrier which constitutes one
`or more accessory ingredients.
`In general, the pharmaceutical
`compositions are prepared by uniformly and intimately bringing the
`active ingredient into association with a liquid carrier or a finely divided
`solid carrier or both, and then, if necessary, shaping the product into the
`desired formulation.
`In the pharmaceutical composition the active
`object compoundis included in the combination in an amountsufficient
`to produce the desired pharmacologic effect upon the process or
`condition of erectile dysfunction...
`
`10
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`15
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`20
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`35
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`-1[1-
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`0013
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`0013
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`

`

`20315PV
`
`
`
`
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`
`The pharmaceutical compositions containing the active
`ingredient suitable for oral administration may be in the form of discrete
`units such as hard or soft capsules, tablets, troches or lozenges, each
`containing a predetermined amountof the active ingredient; in the form
`of a dispersible powder or granules; in the form ofa solution or a
`suspension in an aqueousliquid or non-aqueousliquid; in the form of
`syrups or elixirs; or in the form of an oil-in-water emulsion or a water-
`in-oil emulsion. Compositions intended for oral use may be prepared
`according to any method known to theart for the manufacture of
`pharmaceutical compositions and such compositions may contain one
`or more agents selected from the group consisting of sweetening agents,
`flavoring agents, coloring agents and preserving agents in order to
`provide a pharmaceutically elegant and palatable preparation.
`Solid dosage forms for oral administration include
`capsules, tablets, pills, powders and granules.
`In such solid dosage
`forms, the active compounds are admixed with at least one inert
`pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
`Such dosage forms can also comprise, as is normal practice, additional
`substances other than inert diluents, e.g., lubricating agents such as
`magnesium stearate. In the case of capsules, tablets and pills, the
`dosage forms may also comprise buffering agents.
`Tablets containing the active ingredient in admixture with
`non-toxic pharmaceutically acceptable excipients may also be
`manufactured by known methods. The excipients used may be for
`example, (1) inert diluents such as calcium carbonate, lactose, calcium
`phosphate or sodium phosphate; (2) granulating and disintegrating
`agents, such as corn starch or alginic acid; (3) binding agents such as
`starch, gelatin or acacia; and (4) lubricating agents such as magnesium
`stearate, stearic acid or tale. The tablets may be uncoated or they may be
`coated by known techniques to delay disintegration and absorption in the
`gastrointestinal tract and thereby provide a sustained action over a
`longer period. For example, a time delay material such as glyceryl
`monostearate or glyceryl distearate may be employed. They mayalso be
`coated by the techniques described in the U.S. Pat. Nos. 4,256,108;
`
`10
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`-12-
`
`0014
`
`0014
`
`

`

`20315PV
`
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`.
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`
`5
`
`10
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`15
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`20
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`25
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`30
`
`4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlled
`release.
`
`In some cases, formulations for oral use may be in the form
`of hard gelatin capsules wherein the active ingredient is mixed with an
`inert solid diluent, for example calcium carbonate, calcium phosphate
`or kaolin. They mayalso be in the form of soft gelatin capsules wherein
`the active ingredient is mixed with water or an oil medium, for example
`peanutoil, liquid paraffin,or olive oil.
`Liquid dosage forms for oral administration include
`pharmaceutically acceptable emulsions, solutions, suspensions, syrups,
`andelixirs containing inert diluents commonly used in the art, such as
`water. Besides such inert diluents, compositions can also include
`adjuvants, such as wetting agents, emulsifying and suspending agents,
`and sweetening, flavoring, and perfuming agents.
`Aqueous suspensions normally contain the active materials
`in admixture with excipients suitable for the manufacture of aqueous
`suspensions. Such excipients may be
`1)
`suspending agents such as sodium carboxymethyl-
`cellulose, methylcellulose, hydroxypropylmethy]l-
`cellulose, sodium alginate, polyvinyl-pyrrolidone,
`gum tragacanth and gum acacia;
`dispersing or wetting agents which may be
`(a)
`a naturally-occurring phosphatide such as
`lecithin,
`a condensation product of an alkylene oxide
`with a fatty acid, for example, polyoxyethylene
`stearate,
`acondensation product of ethylene oxide with a
`long chain aliphatic alechol, for example,
`heptadecaethyleneoxycetanol,
`acondensation product of ethylene oxide with a
`partial ester derived from a fatty acid and a
`hexitol such as polyoxyethylenesorbitol
`monooleate, or
`
`(d)
`
`-13-
`
`(2)
`
`(b)
`
`(c)
`
`
`
`0015
`
`0015
`
`

`

`20315PV
`
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`
`(e)
`
`acondensation product of ethylene oxide with a
`parti