US3560625A - Method of,and formulations for,introducing alkoxybenzamides into the systemic circulatory system - Google Patents
Method of,and formulations for,introducing alkoxybenzamides into the systemic circulatory system Download PDFInfo
- Publication number
- US3560625A US3560625A US617058A US3560625DA US3560625A US 3560625 A US3560625 A US 3560625A US 617058 A US617058 A US 617058A US 3560625D A US3560625D A US 3560625DA US 3560625 A US3560625 A US 3560625A
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- United States
- Prior art keywords
- drug
- alkoxybenzamides
- percent
- solvent
- formulations
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- OCSOHUROTFFTFO-UHFFFAOYSA-N styramate Chemical compound NC(=O)OCC(O)C1=CC=CC=C1 OCSOHUROTFFTFO-UHFFFAOYSA-N 0.000 description 1
- 229960001059 styramate Drugs 0.000 description 1
- 231100000212 subchronic toxicity study Toxicity 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
Definitions
- the present invention relates to a means of aleviating pain and, more particularly, to a method of, and formulations for, introducing alkoxybenamides into the systemic circulation system.
- alkoxybenzamides can be introduced into the systemic circulation system through mucous membranes when the membrane is contiguous to a large supply of blood to provide a route of administration comparable to that of the parenteral route of administration.
- R is an alkyl group having 1 to 5 carbon atoms.
- ortho-ethoxybenzamide ortho-ethoxybenzamide (oethoxybenzamide or OEB) represented by the formula:
- OEB has been chosen as the representative of the alkoxybenzamides because it is commercially available and representative of the class defined hereinbefore.
- the drug can be administered at any time and no special need such as water is required.
- the analgesic action of the drug is much greater than that of salicylates and phenactin-like drugs and does not cause gastro-intestinal irritation.
- the experimental analgesic activity of the drug is comparable to certain narcotic drugs, e.g., codeine, but still is not a narcotic and does not possess the toxic side eflects of narcotics.
- the drug can be administered to patients unable to take analgesics per se.
- the most readily accessible mucous membranes contiguous to large supplies of blood are the mucous membrane of the oral or buccal cavity, that of the lungs, the mucous membrane of the rectum and that of the vagina.
- the present method of the formulations for, administrating alkoxybenzamides provides introduction of the benzamide directly into the arterial circulation without involvement of the upper gastrointestinal tract, intravenous or other parenteral routes of administration.
- the advantage of the present method is that passage of the drug through the liver is prevented prior to arrival of the drug at the side of action. Degradation of the drug readily occurs at this site, i.e., the liver, therefore results in a reduction of the available active molecules.
- the present method of contacting a mucous membrane contiguous to the systemic circulatory system assures a greater adsorption of the intact molecule of the drug into the arterial, vascular network and therefore a larger retention of the intact molecules of the drug for delivery to sites within the central nervous system resulting in the induction of analgesia.
- a mucous membrane contiguous thereto such as the lungs
- either a solution of the alkoxybenzamide suitable for use with a nebulizer or an aerosol formulation is used for introduction through the oral mucous into the systemic circulatory system
- a sub-lingual tablet or lozenge can be used.
- For introduction into the systemic circulatory system through the mucous membrane of the vagina or the rectum supporitories or tablets can be used.
- Solvent Maximum concentration, percent Water (cold) 0.05 Water (hot, about F.) 0.10 Ethanol (hot) 5.00 Propylene glycol (hot) 2.00
- the solvent for the ortho-ethoxybenzarnide in addition to being a solvent for the drug must possess these other characteristics (1) it must be a solvent for lipoids and nonpolar materials; (2) it must be non-toxic; and (3) it must be well tolerated by the organism.
- the denominator is the number of test animals; the numerator 1s the number of test animals reacting.
- HOT PLATE REFLEX This reflex is an extension of the flexor withdrawal response, e.g., the occurrence of a painful stimulus results 6 in the animals attempt to escape.
- the stimulus employed is a thermal one. This standard procedure originally was devised by Woolfe and MacDonald and reported in].
- Orthoethoxybenzamide supplied by four manufacturers was tested.
- the OEB was administered by the low pressure aerosol inhalation route (nebulizer) with the results as indicated hereinafter.
- the test mice were exposed for five minutes employing a 0.4% to 0.8% solution as indicated.
- Aerosol inhalation employing nebulizor
- the skin twitch reflex in rabbits is based essentially upon the principle that the latent response of the skin to twitch, when an electrical stimulus is applied, is a function of the animals sensitivity threshold.
- the stimulus is delivered through bipolar platinum electrodes spaced one centimeter apart to the dorsal skin of the animal.
- the power source is a Thomas Square Wave Stimulator which delivers a direct current square wave pulse at 120 c.p.s. with 0.3 msec. pulse delay.
- Each animal is prepared by cleanly shaving the hair from the dorsolumbar area with an electric clipper. Four concentric sites one centimeter in diameter are demarcated with indelible ink; two on either side of the middle.
- the response time is recorded by the observer employing a stop watch.
- the alkoxybenzamide in this instance orthoethoxybenzamide, was administered by placing a mask over the rabbits face, introducing the OEB into the mask from a nebulizer, and allowing the rabbit to inhale the drug for a period of five minutes.
- the assigned dose is an approximation.
- Table V The results are set forth in Table V.
- Electrode site No. Minutes after 1 2 3 4 adminis- Response time 0 EB rug/kg Volts tration seconds 999 992-99 2"??? FNNE"? 0201000 @0000 numb moemoon OOOnhNO 'oooooonc oooemao Electrode site No. Minutes after 1 2 3 4 adminis- Response time,
- a propellant or propellants is used in the high pressure aerosol inhalation method of administering alkoxybenzamides (high pressure relative to the pressure of a nebulizer).
- the propellant(s) and the solvent(s) preferably are mutually soluble.
- the propellant(s) must be non-toxic, must evaporate so rapidly as to produce a relatively dry spray with the result that only dry material, i.e., substantially only the alkoxybenzamide reaches the transport sites, i.e., the mocous membranes of the mouth, trachea, bronchia, and lungs including the alveolar sac.
- the propellant(s) preferably is the liquefied normally gaseous low molecular weight halogenated hydrocarbons, such as halogenated ethane, methane, and/or mixtures thereof.
- halogenated hydrocarbons known in the art as the Freons and Genetrons and the like have been found to be particularly suitable.
- Specific examples of such propellants are dichlorodifiuoromethane (Freon 12), dichlorotetrafiuoroethane (Freon 114), trichloromonofluoroethane (Freon 11), trifluoroethylchloride and monochlorodifluoromethane (Freon 22).
- any fluorinated hydrocarbon propellant or combination of fluorinated hydrocarbon propellants or compressed gas, e.g., nitrous oxide, carbon dioxide, compatible with a suitable co-solevnt system and approved for food and/or drug application can be used.
- the solution of the particular propellant-solvent should be integrated with the type of container and the particular vapor pressure desired.
- compositions Illustrative of the variation in solvents and in propellant composition which have been tested are the following compositions:
- Solvent A percent Wt 40. 0 40. 0 40.0 35. 0 40. 0 00. 0 80. 0 08. 0 00. 0 08.0
- Solvent B percent wt.. 40. 0 40. 0 40.0 35. 0 40.0 0. 0 10.0 12.0 10.0 12.0
- Solvent C percent wt 8.0 8. 0 10. 0 10. 0
- Propellant-solvent A is trichloromonofluorometnane.
- Propellant-solvent B is dichlorodifluoromethane.
- Propellant-solvent C is trifluoroethyl chloride.
- Sample number 4 tends to separate into two distinct layers. However, it is easily dispersed with shaking and operative if shaken before using.
- Sample number 5 is satisfactory though hazy.
- Sample numbers 7 and 8 are satisfactory although each has a tendency to settle into two layers but each is readily dispersed with shaking.
- the areosol compositions samples 1 through 10 were dispensed through Emson M- PFG metering valves discharging 50 milligrams of the aerosol composition per actuation.
- the calculated dosages for the four most satisfactory combinations of ingredients are as follows:
- the concentration of the drug is limited by the concentration which can be dispensed through a specific valve and by its solubility in the propellant-solvent system.
- concentration which can be dispensed through a specific valve and by its solubility in the propellant-solvent system.
- concentration for discharge through Emson M-20 PFG valves the'limiting concentration for ortho-ethoxybenzamide is about 2%.
- the aerosol composition comprises about 2% by weight of ortho-ethoxybenzamide, propellant-solvent 70 to 98% by weight, and auxiliary solvent or co-solvent the balance to make 100%.
- orthoethoxybenzamide given by aerosol inhalation to mice will adequately protect them from writhing induced by an intra-peritoneal injection of para-phenylquinone and also significantly elevate their thermic skin tolerance time threshold.
- dosages of the drug in which the non-Freon propellant system was employed equivalent dosages in a solvent system such as exemplified by the propellant solvent systems of Samples No. 9 and 10 in Table VI were found to produce effects which were comparable.
- the formulation of orthoethoxybenzamide in a solvent system such as described hereinbefore represents a means by which a relatively poorly soluble substance can be dissolved in the propellant solvent system and administered via the aerosol inhalation route.
- 1O laxants e.g., maprobamate, (Chordiazepoxide Hcl).
- the aerosol analgesic composition of the present invention provides rapid onset of action with minimal dosage, reduced side effects, and a convenient and esthetically more attractive form of medication.
- the efficacy of the route of administration provided by the sublingual tablet has been demonstrated and may be related to the rapid absorption and transportation of the drug to its locus of action before going to the liver where it is chemically altered.
- the intactness of the drug molecule and its delivery to the site of action are directly related to the route of administration.
- this route of administration because of its augmenting action on potency, allows for a reduced amount to be employed for therapeutic value. Therefore, this route of administration reduces the possibility of side effects.
- the advantages of the use of a sublingual tablet for the admininstration of orthoethoxybenzamide are (1) rapid onset of drug activity; (2) more potent and prolonged actions from the drug because it is not chemically altered by the liver before arriving at the site of the action; and (3) a reduced amount is required since oral trans-mucosal absorption is complete within minutes in contrast to gastro-intestinal absorption in which about fifty percent of the drug is absorbed within six hours.
- the sublingual administration of orthoethoxybenzamide has the following advantages over the oral method of administration previously recommended; (1) the drug can be administered at any time without any need for assisting means such as potable water to wash the drug from the mouth, (2) the action of the orthoethoxybenzamide in smaller doses is much greater than that of orally administered salicylates and phenacetin-like drugs and does not cause gastrointestinal irritation; (3) the analgesic effectiveness of the drug is comparable to that of certain narcotic drugs, e.g., codeine, but without the hazards of the narcotic side effects, (4) the administration of orthoethoxybenzamide by this route is especially beneficial in relieving pain which is refractive to salicylates and other non-narcotic agents.
- formulations 4, 5 and 6 contain- It is within the purview of the present invention to ing no PVP exhibit greater disintegrating capabilities incorporate other analgesic drugs, e.g., acetylsalicyclic acid; anti-histamines, fig chloropheniramine, Benadryl; [Z-(diphenylmethoxy) N,N dimethylethylamine hydrochloride]; bronchodilators, e.g., isoproterenol, ephedrine; sedatives, e.g., pentobarbital; centrally acting muscle rethan the formulation 1 in which there is PVP.
- formulation 6 represents a more refined and acceptable dosage form.
- Milligrams per tablet can be made as required.
- therapeutic Cyclamate Sodium, N.F. Zero to about 20.0. amounts of steroids, antihistamines, broncho-dilators, Saccharine Sodium, U.S.P. Zero to about 5.0.
- Flavors Zero to about 10.0. may be absorbed sublingually or via the gastro-intesti- Starch, micro Zero to about 15.0. nal tract if delayed and additional absorption is desired: Urea, N.F. Zero to about 10.0.
- steroids dexamethane sulfate
- antihistamines chlorophen- Incorporation of other analgesic durgs steroids anti lramme .maleate
- bronchodllator lsoproterepol pamsym' histamines broncho-dilators, parasympatliolytic aiitituspatholytlc agent atropme sulfate
- antltu repet sive sedative and/or muscle relaxants in an br all of tromethorphan HBr are examples of drugs that may be the formulations set forth herein can be s ⁇ ?
- a densifier Such as PVP an contiguous thereto as illustrated he rembefor e or through cipient such as lactose siiccrose and a die lubricant such th?
- Orthoethoxybenzamide About 10 to about 100. 27 using commercially available orthoethoxybenzamide, for- Polyvinylpyrrolidone Zero to about 2.5. mulations in the ranges set forth in Table VIII are use- Starch, arrowroot About 7 to about 14.0. ful.
- Polyethylene glycol 1000 (watersoluble polyethylene glycol polymer,mol. ⁇ vt.950to 1,050) 35.00-90.00 1. 00-40. 00
- Polyethylene glycol 4000 (watersoluble polyethylene glycolpolymer, mol. wt. 3,000 to 3,700) 1. 00-15. 00 1, 00-70. 00
- Glycerol monostearate 165 (acidstable, sell-emulsifying glycerol monostearate) 1. 00-30. 00
- Absolute ethanol-Ethanol USP can be used.
- Propylene glycol-Absolute ethanol or Ethanol USP can be used in whole or in part.
- Ethanal USP can be used in whole or in par Dilluorodiehloromethane-Diiluoromonochloromethane, octofluoroeyclobutane can be used in whole or in part.
- mice0starel1Arro ⁇ vroot starch, potato starch, purified talc can be used in whole or in part.
- Magnesium stearatcSodium stcarate, tale, stearic acid can be used in whole or in part.
- UreaSulka Floc purified cellulose
- aminoacctic acid aminoacctic acid
- earboxymethylcellulose acid can be used in whole or in part.
- Cyclamate sodiu1nHexamic acid, sucrose, mannitol can be used in whole or in part.
- saccharine sodium-Saccharine calcium can be used in whole or in part.
- Sorbitol solution-Glycerin can be used in whole or in part.
- Polyethylene glycol 1000-Theobroma oil, polyethylene glycol 1540, polyethylene glycol 6000, glycerine, gelatin can be used in whole or in part.
- Mineral oil0live oil, glycerin, cottonseed oil can be used in whole or in part.
- Glycerol monostearate -Sodium Oleate, trlethauolamine oleate can be used in Whole or in part.
- oral ingestion would be indicative that sublingually the drug is self limiting.
- a method of administering ortho-ethoxybenzamide which comprises introducing into the oral cavity to con- 40 tact a mucous membrane contiguous to the systemic circulatory system a composition comprising a therapeutically effect amount of ortho-ethoxybenzamide in a nontoxic pharmaceutical carrier adapted to provide rapid and substantially complete absorption of said orthoethoxybenzamide when in contact with said mucous membrane, said composition being in the form of a sublingual tablet.
- said tablet comprises about 0.10 to about 99.0% by weight of orthoethoxybenzamide and the balance, to make 100% by weight, of said carrier.
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Abstract
ALKOXYBENZAMIDE ANALGESICS ARE INTRODUCED INTO THE SYSTEMIC CIRCULATION SYSTEM VIA A CONTIGUOUS MUCOUS MEMBRANE TO INCREASE ONSET OF ACTIVITY, POTENCY, ETC.
Description
United States Patent Ofliee 3,560,625 METHOD OF, AND FORMULATIONS FOR, INTRO- DUCING ALKOXYBENZAMIDES INTO THE SYSTEMIC 'CIRCULATORY SYSTEM Christopher Hollet Costello, Summit, N.Y., and Salvatore Joseph De Salva, Somerset, and John Phillip Ryan, New Brunswick, N.J., assignors to Colgate-Palmolive Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 20, 1967, Ser. No. 617,058 Int. Cl. A61k 27/00 US. Cl. 424-324 ABSTRACT OF THE DISCLOSURE Alkoxybenzamide analgesics are introduced into the systemic circulation system via a contlguous mucous membrane to increase onset of activity, potency, etc.
BACKGROUND OF THE INVENTION The present invention relates to a means of aleviating pain and, more particularly, to a method of, and formulations for, introducing alkoxybenamides into the systemic circulation system.
The conventional method of introducing ana gesic substances into the systemic circulatory system is through oral ingestion and the gastro-intestinal tract. However, as explained in Drills Pharmacology in Medicine, 3rd edition, McGraw-Hill, New York, NY. (1. S. D. Palma, editor), pp. 297498, salicylates and derivatives thereof are subject to chemical alteration in the liver. The chemical alteration of the alkoxybenzamide molecule reduces the potency of the drug. On the other hand, the poor solubility of alkoxybenzamides in common fluids for injection (e.g., normal saline, dextrose for injection and the like) prohibits the use of alkoxybenzamides in an injectable form, other than that of a dilute suspension, with any degree of safety or confidence in humans. Therefore, experiments concerned with the parenteral use of alkoxybenzamides such as ortho-ethoxybenzamide in humans for analgesic activity have not been performed. However, it has now been discovered that alkoxybenzamides can be introduced into the systemic circulation system through mucous membranes when the membrane is contiguous to a large supply of blood to provide a route of administration comparable to that of the parenteral route of administration. Thus, for example, in the article entitled Investigations of o-Ethoxyben-zamide (Ethosalicyl) a New Salicyl Derivative by F. Ducco, S. de Vercelli and R. Strobbia, published in Gazetta Medica Italian, 114, No. 5 (1955), pp. 93-99, it was reported that the effective oral dosage of o-ethoxybenzamide to relieve the pain of acute articular rheumatism, arthritis, etc., was in the range of one to four (1-4) grams. It has been shown that when contacted with a mucous membrane such as that of the oral cavity in the form of a sublingual tablet the effective analgesic dose is in the range of fifty to two hundred (50-200) milligrams, i.e., in the range of 0.71 to a maximum of 4 milligrams per kilogram, that is the efficacy of the o-ethoxybenzamide is increased at least twenty times (1000/50=20). Furthermore, in a 4 Claims 7 3,560,625 Patented Feb. 2, 1971 sub-lingual toxicity study of three months duration data was obtained tending to establish that the mucosal method of administration of alkoxybenzamides prec udes the possibility of an overdose.
SUMMARY OF THE INVENTION As those skilled in the art know the alkoxybenzamides can be represented by the following formula:
C ONHz where R is an alkyl group having 1 to 5 carbon atoms.
Representative, and presently the most readily obtained of the alkoxybenzamides is ortho-ethoxybenzamide (oethoxybenzamide or OEB) represented by the formula:
CONH2 Accordingly, OEB has been chosen as the representative of the alkoxybenzamides because it is commercially available and representative of the class defined hereinbefore.
The present method and formulations of alkoxybenzamides for introducing alkoxybenzamides into the systemic circulation have a number of advantages of the methods and formulations known heretofore. These ad vantages are enumerated as follows:
(1) Rapid onset of drug activity with minimum dosage.
(2) Reduction in side effects.
(3) More potent action from the drug because it is not chemically altered by the liver before arrival at the site of action.
(4) Smaller dosage required since the transmucosal adsorption is rapid and complete in contrast to gastrointestinal adsorption in which only about fifty (50) percent of the drug is adsorbed within six hours. (C. Davidson, J. Wangler and P. K. Smtih, J. Pharm. Exp. Therap., 136, pp. 226-23 1, 1962.)
(5) The drug can be administered at any time and no special need such as water is required.
(6) The analgesic action of the drug is much greater than that of salicylates and phenactin-like drugs and does not cause gastro-intestinal irritation.
(7) The experimental analgesic activity of the drug is comparable to certain narcotic drugs, e.g., codeine, but still is not a narcotic and does not possess the toxic side eflects of narcotics.
(8) By administration through contact with a mucous membrane the drug is especially beneficial in relieving pain "and in particular pain due to skeletal muscular origin.
(9) The drug can be administered to patients unable to take analgesics per se.
The most readily accessible mucous membranes contiguous to large supplies of blood are the mucous membrane of the oral or buccal cavity, that of the lungs, the mucous membrane of the rectum and that of the vagina.
Thus, the present method of the formulations for, administrating alkoxybenzamides provides introduction of the benzamide directly into the arterial circulation without involvement of the upper gastrointestinal tract, intravenous or other parenteral routes of administration. The advantage of the present method is that passage of the drug through the liver is prevented prior to arrival of the drug at the side of action. Degradation of the drug readily occurs at this site, i.e., the liver, therefore results in a reduction of the available active molecules. The present method of contacting a mucous membrane contiguous to the systemic circulatory system assures a greater adsorption of the intact molecule of the drug into the arterial, vascular network and therefore a larger retention of the intact molecules of the drug for delivery to sites within the central nervous system resulting in the induction of analgesia. For introduction into the systemic circulatory system through a mucous membrane contiguous thereto, such as the lungs, either a solution of the alkoxybenzamide suitable for use with a nebulizer or an aerosol formulation is used. For introduction through the oral mucous into the systemic circulatory system a sub-lingual tablet or lozenge can be used. For introduction into the systemic circulatory system through the mucous membrane of the vagina or the rectum supporitories or tablets can be used.
DESCRIPTION OF THE PREFERRED EMBODIMENTS Formulations for introducing alkoxybenzamide by any of the foregoing methods are illustrated by the formulations of o-ethoxybenzamide set forth in Table I.
Then the A01 dose in milligrams per kilogram is Thus, the dosage in 10% propylene glycol solution to provide protection in of the mice subjected to the phenylquinone writhing assay by the three routes is given in the following comparison:
Route: Mg./kg.
Oral-gastro-intestinal 6.2. Intra-peritoneal 3.2. Aerosol (by Chamber Method) 4.2 maximum possible.*
*Those skilled in the art readily understand that all of the drug sprayed into the exposure chamber is not inhaled by the subject animal. However, the value given is based upon the total amount of material sprayed into the chamber.
The problem of providing an aerosol spray for inhalation of ortho-ethoxybenzamide involves finding a solvent TABLE I Percent by weight Formulation No I II III IV V VI VII VIII o-Ethoxybenzamide .0 12.0 10.0 100.0 5.0 7.0 Absolute ethanol. .0 Propylene glycol Diehloromonofiuoro-methane Dichlorodiflnoro-methanc Deionized water Micro starch Urea Magnesium stearat Cyclamate sodium saccharine sodium Sorbltol solution USP- Flavors Polyethylene glycol 1000 Polyethylene glycol 4000. Mineral oil Glycerol monostearate.
Total NOTE. IAe1'0s0l (Ilnorinated hydrocarbon type) II-Acros0l (nebulizcr type) llISub-lingual tablets IV-Supposltorios V-Suspensions VIP0wders VIILotions VIII-Creams.
C=concentration of the drug in the material sprayed into the chamber,
for the drug. The solubility of ortho-ethoxybenzamide in three solvents is set forth in the following tabulation:
Solvent: Maximum concentration, percent Water (cold) 0.05 Water (hot, about F.) 0.10 Ethanol (hot) 5.00 Propylene glycol (hot) 2.00
It is manifest that hot ethanol is the best solvent. On the other hand, a mixture containing more than about 18% of ethanol by weight produces an unpleasant oral reaction which can more than counterbalance the efficacy of the inhalatory route. Therefore, the solvent for the ortho-ethoxybenzarnide in addition to being a solvent for the drug must possess these other characteristics (1) it must be a solvent for lipoids and nonpolar materials; (2) it must be non-toxic; and (3) it must be well tolerated by the organism.
TABLE II [Low pressure aerosol inhalation (nebulizer)] Test Method: Phenylquinone induced writhing reflex.
Number of Animals (each test): 8 Phenylquinne-0.25 millileters of 0.014 percent solution.
Time (minutes) after I tretchadministered) ing OEB administered Writhing Test No. 1
Test N0. 3
10 8/8 8/8 mgJkg. as 0.8% solution 8/8 8/8 2/8 2/8 Test No. 4
8/8 8/8 10 mg./kg. as 0.4% solution 8/8 8/8 3/8 3/8 8/8 8/8 0. 1 mgJkg. as 0.04% solution- 8/8 8/8 340-60 6/8 6/8 A detailed description of this method is given Proc. Soc. Exp. Biol. Med. 95, 729 (1957) E. Siegmund, E et a1.
2 The denominator is the number of test animals; the numerator 1s the number of test animals reacting.
3 Mg./kg. as usual is milligrams of OEB per kilogram of animal body weight.
HOT PLATE REFLEX This reflex is an extension of the flexor withdrawal response, e.g., the occurrence of a painful stimulus results 6 in the animals attempt to escape. The stimulus employed is a thermal one. This standard procedure originally was devised by Woolfe and MacDonald and reported in]. Pharmacol. Exp. Therap. 80, 300 (1944) in a paper entitled The Evaluation of the Analgesic Action of Pethidine Hydrochloride (Demerol).
Orthoethoxybenzamide supplied by four manufacturers was tested. The OEB was administered by the low pressure aerosol inhalation route (nebulizer) with the results as indicated hereinafter. The test mice were exposed for five minutes employing a 0.4% to 0.8% solution as indicated.
TABLE III [Average reflex time in seconds for 10 animals] OEB OEB sample N0. a/ a.
as 0.8% Control 1 2 3 4 Test N0 SPONTANEOUS MOTOR ACTIVITY Spontaneous motor activity was determined for mice by employing the Woodward Activity Recorder. The Woodward activity instrument consists of three separate circular units each having a diameter of twelve inches and a circular housing five and one-half inches in diameter which contains a photoelectric cell and six ports. Spontaneous motor activity is registered as a function of the number of times the light beam from each of the ports is interrupted by placing three mice in each unit for up to sixty minutes and recording the number of times the light beams were interrupted fifteen minutes after administration of the drug and at the end of sixty minutes. The results are presented in Table IV.
TABLE IV 15 min. after min. after administration administration Average Average OEB, mg./kg. Route Counts count Counts count Cage No.:
1 Control 1, 666 555 838 279 2 20 I.P. 562 187 156 52 3-- 20 I.P 555 438 146 1 Control 1,083 361 1,675 558 2 10 I.P 384 128 1,323 441 3 10 I.P. 1,038 346 1,410 470 1 Control 1, 300 433 903 301 2 1 LP. 2 1,526 509 1, 296 432 3 1 LP. 1, 745 582 1, 674 588 1.. Control 1,301 434 1,239 413 2 1 AEI 3 2 1. 713 471 1, 536 512 3 1 AEI 2 1,988 663 1,356 452 1 Control 1, 504 501 1, 245 415 2 20 as 0.8% AEI 2 1,481 494 1, 449 483 3.. Solution AEI 3 1,872 624 1,829 610 1 Control 1, 326 442 1, 407 469 2 10 as 0.4% .AEI 2 1,407 469 1, 532 511 3 Solution AEI 2 1, 502 501 1,328 442 1 Intraperitoneal.
2 It is known that at low dosage levels certain central nervous system depressant drugs, i.e., phenobarbital, do not produce depression, but do exhibit excitement. The excitement produced by aerosol administration (low dosage level due to incomplete adsorption from the administration chamber) is analagous to that produced by phenobarbital at low doses.
Aerosol inhalation (employing nebulizor).
7 SKIN TWITCH REFLEX The skin twitch reflex in rabbits is based essentially upon the principle that the latent response of the skin to twitch, when an electrical stimulus is applied, is a function of the animals sensitivity threshold. The stimulus is delivered through bipolar platinum electrodes spaced one centimeter apart to the dorsal skin of the animal. The power source is a Thomas Square Wave Stimulator which delivers a direct current square wave pulse at 120 c.p.s. with 0.3 msec. pulse delay. Each animal is prepared by cleanly shaving the hair from the dorsolumbar area with an electric clipper. Four concentric sites one centimeter in diameter are demarcated with indelible ink; two on either side of the middle. The response time is recorded by the observer employing a stop watch. The alkoxybenzamide, in this instance orthoethoxybenzamide, was administered by placing a mask over the rabbits face, introducing the OEB into the mask from a nebulizer, and allowing the rabbit to inhale the drug for a period of five minutes. The assigned dose is an approximation. The results are set forth in Table V.
TABLE V Electrode site No. Minutes after 1 2 3 4 adminis- Response time, 0 EB rug/kg Volts tration seconds 999 992-99 2"??? FNNE"? 0201000 @0000 numb moemoon OOOnhNO 'oooooonc oooemao Electrode site No. Minutes after 1 2 3 4 adminis- Response time,
0 EB, mg./kg. Volts tration seconds Control 4 1. 2 1. 0 1. 0 1. 0 4 10 2.0 1.8 2.2 2.2 20 1. 8 l. 0 1. 6 1. 8 1.0 1.2 1.0 1.2
0.8 0.6 0.0 0.0 1. 6 1.8 1. 0 l. G l. 0 1. 0 l. 2 1. 0 40 0. 8 0. 6 0. 0 O. 8
Control 6 0. 4 0. 2 0. 4 0. 2 6 10 1. 2 1. 4 1. 2 1. 2 20 0. 6 0. 8 0. 6 0. 8 40 0.2 0.4 0.2 0.2
Control 7 0. 2 0.2 0. 2 0. 2 7 10 0. 4 0. 6 0. 6 0. 2 20 0. 2 0. 4 0. 4 0. 4 40 0. 2 0. 2 0. 2 0. 2
HIGH PRESSURE AEROSOL INHALATION In the high pressure aerosol inhalation method of administering alkoxybenzamides (high pressure relative to the pressure of a nebulizer) a propellant or propellants is used. The propellant(s) and the solvent(s) preferably are mutually soluble. The propellant(s) must be non-toxic, must evaporate so rapidly as to produce a relatively dry spray with the result that only dry material, i.e., substantially only the alkoxybenzamide reaches the transport sites, i.e., the mocous membranes of the mouth, trachea, bronchia, and lungs including the alveolar sac.
The propellant(s) preferably is the liquefied normally gaseous low molecular weight halogenated hydrocarbons, such as halogenated ethane, methane, and/or mixtures thereof. The halogenated hydrocarbons known in the art as the Freons and Genetrons and the like have been found to be particularly suitable. Specific examples of such propellants are dichlorodifiuoromethane (Freon 12), dichlorotetrafiuoroethane (Freon 114), trichloromonofluoroethane (Freon 11), trifluoroethylchloride and monochlorodifluoromethane (Freon 22). In general, any fluorinated hydrocarbon propellant or combination of fluorinated hydrocarbon propellants or compressed gas, e.g., nitrous oxide, carbon dioxide, compatible with a suitable co-solevnt system and approved for food and/or drug application can be used. In addition to the propellantsolvent characteristics given hereinbefore, the solution of the particular propellant-solvent should be integrated with the type of container and the particular vapor pressure desired.
Illustrative of the variation in solvents and in propellant composition which have been tested are the following compositions:
TABLE VI Sample No.
Component 1 2 3 4 5 6 7 8 0 10 o-Ethoxybenzamide, percent wt 2.0 2.0 2.0 1.6 2.0 2.0 2.0 2.0 2.0 Propylene glycol, percent wt 9. 0 18. 0 10. 0 9. 2 9. 0 Absolute alcohol, percent wt 18.0 9.0 18.0 9.2 9.0 18.0 18.0 Propellant:
Solvent A, percent Wt 40. 0 40. 0 40.0 35. 0 40. 0 00. 0 80. 0 08. 0 00. 0 08.0 Solvent B, percent wt.. 40. 0 40. 0 40.0 35. 0 40.0 0. 0 10.0 12.0 10.0 12.0 Solvent C, percent wt 8.0 8. 0 10. 0 10. 0
Propellant-solvent A is trichloromonofluorometnane. Propellant-solvent B is dichlorodifluoromethane. Propellant-solvent C is trifluoroethyl chloride.
Sample numbers 1 and 2. have a tendency to crystallize but this is slight.
Sample number 4 tends to separate into two distinct layers. However, it is easily dispersed with shaking and operative if shaken before using.
Sample number 5 is satisfactory though hazy.
Sample number 6 is satisfactory.
Sample numbers 7 and 8 are satisfactory although each has a tendency to settle into two layers but each is readily dispersed with shaking.
Sample numbers 9 and 10 are satisfactory.
The areosol compositions samples 1 through 10 were dispensed through Emson M- PFG metering valves discharging 50 milligrams of the aerosol composition per actuation. The calculated dosages for the four most satisfactory combinations of ingredients are as follows:
The concentration of the drug is limited by the concentration which can be dispensed through a specific valve and by its solubility in the propellant-solvent system. For example, for discharge through Emson M-20 PFG valves the'limiting concentration for ortho-ethoxybenzamide is about 2%.
From the foregoing it is manifest that the aerosol composition comprises about 2% by weight of ortho-ethoxybenzamide, propellant-solvent 70 to 98% by weight, and auxiliary solvent or co-solvent the balance to make 100%.
Suspensions of alkoxybenzamide in excess of two percent and the balance propellant or propellant-solvent can be used employing valve systems such as the Newman- Green or Valve Corporation of America.
Pharmacological evaluation has shown that orthoethoxybenzamide given by aerosol inhalation to mice will adequately protect them from writhing induced by an intra-peritoneal injection of para-phenylquinone and also significantly elevate their thermic skin tolerance time threshold. When compared with dosages of the drug in which the non-Freon propellant system was employed equivalent dosages in a solvent system such as exemplified by the propellant solvent systems of Samples No. 9 and 10 in Table VI were found to produce effects which were comparable. The formulation of orthoethoxybenzamide in a solvent system such as described hereinbefore represents a means by which a relatively poorly soluble substance can be dissolved in the propellant solvent system and administered via the aerosol inhalation route.
1O laxants, e.g., maprobamate, (Chordiazepoxide Hcl).
The aerosol analgesic composition of the present invention provides rapid onset of action with minimal dosage, reduced side effects, and a convenient and esthetically more attractive form of medication.
SUB-LINGUAL TABLET It has been demonstrated in the study upon which the present invention is based on that the sublingual and/or buccal administration of orthoethoxybenzamide using a tablet with rapid disintegration capabilities facilitates the absorption of the drug through the oral mucosa directly into the systemic circulatory system. This action results in an augmentation of the pharmacological action of the drug beyond that which could be anticipated by the conventional use of oral ingestion and absorption through the gastro-intestinal tract.
The efficacy of the route of administration provided by the sublingual tablet has been demonstrated and may be related to the rapid absorption and transportation of the drug to its locus of action before going to the liver where it is chemically altered. The intactness of the drug molecule and its delivery to the site of action are directly related to the route of administration. Moreover, this route of administration, because of its augmenting action on potency, allows for a reduced amount to be employed for therapeutic value. Therefore, this route of administration reduces the possibility of side effects. Thus, the advantages of the use of a sublingual tablet for the admininstration of orthoethoxybenzamide are (1) rapid onset of drug activity; (2) more potent and prolonged actions from the drug because it is not chemically altered by the liver before arriving at the site of the action; and (3) a reduced amount is required since oral trans-mucosal absorption is complete within minutes in contrast to gastro-intestinal absorption in which about fifty percent of the drug is absorbed within six hours.
The sublingual administration of orthoethoxybenzamide has the following advantages over the oral method of administration previously recommended; (1) the drug can be administered at any time without any need for assisting means such as potable water to wash the drug from the mouth, (2) the action of the orthoethoxybenzamide in smaller doses is much greater than that of orally administered salicylates and phenacetin-like drugs and does not cause gastrointestinal irritation; (3) the analgesic effectiveness of the drug is comparable to that of certain narcotic drugs, e.g., codeine, but without the hazards of the narcotic side effects, (4) the administration of orthoethoxybenzamide by this route is especially beneficial in relieving pain which is refractive to salicylates and other non-narcotic agents.
Illustrative formulations which have provided satisfactory results are as follows:
styramate or Librium TABLE VII Formulation No.
Mg./ Percent; Mg./ Percent Mg./ Percent Mg./ Percent Mg./ Percent Mg./ Percent Components tablet w./w. tablet w./w. tablet w./w. tablet w./w. tablet w./w. tablet w./w Orthoethoxy-benzamide. 10.0 16.7 25.0 41. 7 50.0 83 3 0 100.0 100.0 71.70
Cyelamate sodium Sa ccharine sodium- Flavors Micro starch actose Polyvinylpyrrolidone Total mgs./percent w./w
It is to be noted that formulations 4, 5 and 6 contain- It is within the purview of the present invention to ing no PVP exhibit greater disintegrating capabilities incorporate other analgesic drugs, e.g., acetylsalicyclic acid; anti-histamines, fig chloropheniramine, Benadryl; [Z-(diphenylmethoxy) N,N dimethylethylamine hydrochloride]; bronchodilators, e.g., isoproterenol, ephedrine; sedatives, e.g., pentobarbital; centrally acting muscle rethan the formulation 1 in which there is PVP. Further, formulation 6 represents a more refined and acceptable dosage form. It provides improved tablet disintegration, due to addition of micro starch and flavor improvement enhances aesthetic value. These capabilities augment drug 11 12 absorption; substitutions and additions to the formula Component: Milligrams per tablet can be made as required. Magnesium Stearate, U.S.P. About 0.5 to about 1.0. There can also be incorporated in the sublingual tab- Lactose, U.S.P. Zero to about 50.0. let, in addition to the alkoxybenzamidc, therapeutic Cyclamate Sodium, N.F. Zero to about 20.0. amounts of steroids, antihistamines, broncho-dilators, Saccharine Sodium, U.S.P. Zero to about 5.0. parasympatholytic and antitussives and other drugs which Flavors Zero to about 10.0. may be absorbed sublingually or via the gastro-intesti- Starch, micro Zero to about 15.0. nal tract if delayed and additional absorption is desired: Urea, N.F. Zero to about 10.0. steroids, dexamethane sulfate; antihistamines, chlorophen- Incorporation of other analgesic durgs steroids anti lramme .maleate; bronchodllator lsoproterepol pamsym' histamines, broncho-dilators, parasympatliolytic aiitituspatholytlc agent atropme sulfate; and antltussant sive sedative and/or muscle relaxants in an br all of tromethorphan HBr are examples of drugs that may be the formulations set forth herein can be s}? to i For introducing alkoxybenzamides in which the alose skilled in the art w1ll recogmze that the subkoxy mu has not more than five carbon atom into lingual tablet of the present invention comprises a therath I t th h peutic concentration of alkoxybenzamide, a disintegrate ema 1c clrcu apry mug Ir-luscous mam rams g agent Such as Starch a densifier Such as PVP an contiguous thereto as illustrated he rembefor e or through cipient such as lactose siiccrose and a die lubricant such th? 5km In addition t9 the nebuhzcr s9lutlons aerosol as magnesium stearate 1rlnlxtuil'oesf, and the sublmgual tablet specificaly described erem e ore suppos1tor1es, suspensions, pow ers, otions an of fifty to about two hundred and eighty (280) m1ll1- TABLE VII grams, i.e., about 0.71 to about 4 milligrams per kilo- Component: Milligrams per tablet gram of body Weight can be used. Thus, for example,
Orthoethoxybenzamide About 10 to about 100. 27 using commercially available orthoethoxybenzamide, for- Polyvinylpyrrolidone Zero to about 2.5. mulations in the ranges set forth in Table VIII are use- Starch, arrowroot About 7 to about 14.0. ful.
TABLE VIII Formulation Number I II III IV V VI VII VIII Aerosol (fluiniinilted fxmlqsql' Sublingu'tl Supposii gli agi tablets tories Suspensions Powders Lotions Creams (1) o-Etlioxybcnzamide 0. 01-5. 00 0.01-8.00 0. 10-00. 00 0. 10-50. 00 0 5050.00 010-10000 0. 50-50. 00 050-50. 00 (2) Absolute etl1anol.. 0. 0020. 00 0. 1015. 00 1.00-40 00 (3) Propylene glycol (1,2-propaned1ol). (4) Monofluorotrichloromethaue. (5) Diiluorodichloromethane. (6) Deionized water (7) Microstarch" (modified wheat starch). (8) Urea (9) Magnesium stearate (10) Cyclamate sodium (sodium cycloliexanesuliamate) 0. 10-16. 00 (11) Saccharine sodium (2,3-dehydro-3- oxobenzisosulionazol sodium) 0. 10-2. 0 (12) Sorbitol solution, sorbitol by weight (D-sorbitol, D-glueitol) 50. 00-99. 50 (13) Flavors 0.0015.00 0.0015.00 0.00-15.00
(14) Polyethylene glycol 1000 (watersoluble polyethylene glycol polymer,mol.\vt.950to 1,050) 35.00-90.00 1. 00-40. 00
(15) Polyethylene glycol 4000 (watersoluble polyethylene glycolpolymer, mol. wt. 3,000 to 3,700) 1. 00-15. 00 1, 00-70. 00
(16) Mineral oil (liquid petrolatum, liquid parafim) 1. OO30. 00
(17) Glycerol monostearate 165 (acidstable, sell-emulsifying glycerol monostearate) 1. 00-30. 00
Total 100. 00 100. 00 100. 00 100. 00 100. 00 100. 00 100. 00 100. 00
*IIercules Powder Company, mierostarch analysis:
Determination Analysis Moisture l1. 0 pH 5. 2 E.E. Fat, percent. 0. 24 Ash, percent 0. 54 Protein, percent. 0. 64 S02, percent 0. 005 Viscosity:
Scott 56/15 Brookfield, cps 545 Granulation, percent on U.S. standard screen:
'lraco 1. 6 200 2. 6 Through 200 45. 8 Nora-For:
Absolute ethanol-Ethanol USP can be used.
Propylene glycol-Absolute ethanol or Ethanol USP can be used in whole or in part.
Monoiluorotiichloromethane-Dichlorotetrafluoroethane, trichlorotrlfiuoroethane, triiluoroutllylehlorido. Ethanal USP can be used in whole or in par Dilluorodiehloromethane-Diiluoromonochloromethane, octofluoroeyclobutane can be used in whole or in part.
Micr0starel1Arro\vroot starch, potato starch, purified talc can be used in whole or in part.
Magnesium stearatcSodium stcarate, tale, stearic acid can be used in whole or in part.
UreaSulka Floc (purified cellulose), aminoacctic acid, earboxymethylcellulose acid can be used in whole or in part.
Cyclamate sodiu1nHexamic acid, sucrose, mannitol can be used in whole or in part.
saccharine sodium-Saccharine calcium can be used in whole or in part.
Sorbitol solution-Glycerin can be used in whole or in part.
Polyethylene glycol 1000-Theobroma oil, polyethylene glycol 1540, polyethylene glycol 6000, glycerine, gelatin can be used in whole or in part.
Mineral oil0live oil, glycerin, cottonseed oil can be used in whole or in part.
Glycerol monostearate -Sodium Oleate, trlethauolamine oleate can be used in Whole or in part.
As stated hereinbefore, there is evidence that the administration of alkoxybenzamides through the mucosa precludes the possibility of an overdose. The foregoing statement is corroborated by the following data involving acute human toxicity studies and chronic and subchronic animal studies.
(1) Acute human toxicity studies via the sublingual route, at doses ranging up to 2,500 to 3,000 mg. per subject have been performed involving 12 healthy males. The drug was administered under monitored conditions and did not produce overt toxic responses,
(2) Chronic and sub-chronic toxicity studies involving dogs which received up to 600 mg./kg. of the drug sublingually, have revealed no obvious toxic behavioral manifestations.
(3) Chronic toxicity studies involving rats wherein the drug is given by oral ingestion have revealed some influence on body weight gain rate.
(4) The dog and rat experiments are being carried out simultaneously and therefore the apparent toxic elfect by for the most part demonstrated less drug available in the blood at the 5 and 180 minute interval.
TABLE IX 5 Time sample Animal withdrawn (minutes after Colony Test introduction No. No. of compound) Results 233 A1 15 Trace of aromatic compound. A2 30 o.
A; 60 None detected.
234 B1 Do. B2 30 D0. a 60 15 212 Cr 15 None detected.
*Slnce more than one aromatic compound can absorb ultraviolet light at the samti wave length and since also the plotted curve from the sample B3 was not distinct or specific for the peak absorbauce obtained, it can only be stated that an aromatic compound or compounds as a concentration of 18.0 meg/ml. of plasma were present.
TABLE X Mg. percent blood level/given time (after drug introduction) 510 min. 30 min. 60 min. 3 hour Weight, Dose,
lbs gm. Sub l Oral Sub Oral Sub Oral Sub Oral 24 {1. 0 0. 69 0. 0 0. 0 1. 40 1. 04 l. 60 1. 97 0. 0 6. 0 0. 0 1. 90 4. 25 3. 25 3. 00 0. 0 my {1. 0 1. 98 0. 0 2. 33 2. 44 2. 68 2. 56 5. 0 2.10 1. 90 5. 50 4. 75 4. 50 1. 10 0. 0 18 {1. 0 1.160 1.00 l. 90 l. 3.0 0. 0 0. 0 5. 0 1. 60 1. 90 4. 00 4. 60 3. 40 3. 90 2. 50 21 0.5 0.0 0.0 0.0 0.0
1 Subllngual. 2 Trace.
oral ingestion would be indicative that sublingually the drug is self limiting.
(5,) The effectiveness of sublingual application of the drug is supported by the following experiments in dogs.
(a) Three dogs, two treated with the drug sublingually and one control dog treated with placebo material, sublingually were selected from a chronic toxicity study colony. The treated dogs had received the drug over a six months interval and are currently receiving 600 mg./kg. The drug was found in the blood of the treated animals but none was found in the blood of the placebo treated animal.
(b) Four sibling dogs of the same litter (Table X) were administered doses of 50, 100 and 500 mg./kg. by both oral and sublingual routes. Blood samples were taken from the jugular vein at 5, 30, 60 and 180 minutes past administration.
The blood samples from animals which received the drug sublingually provided detectable amounts of the drug at the 5 'through 180 minute intervals whereas the same animals given the drug orally at the same dosage What is claimed is: 1. A method of administering ortho-ethoxybenzamide which comprises introducing into the oral cavity to con- 40 tact a mucous membrane contiguous to the systemic circulatory system a composition comprising a therapeutically effect amount of ortho-ethoxybenzamide in a nontoxic pharmaceutical carrier adapted to provide rapid and substantially complete absorption of said orthoethoxybenzamide when in contact with said mucous membrane, said composition being in the form of a sublingual tablet. r
2. A method as set forth in claim 1 wherein said amount of ortho-ethoxybenzamide is sufficient to provide a dose of at least 50 milligrams.
3. A method as set forth in claim 1 wherein said membrane is in the oral cavity, said carrier includes a mixture of starch disintegrating agent and flavor.
4. A method as set forth in claim 3 wherein said tablet comprises about 0.10 to about 99.0% by weight of orthoethoxybenzamide and the balance, to make 100% by weight, of said carrier.
References Cited UNITED STATES PATENTS 2,782,975 2/1957 Bird 167-65N 3,050,443 8/1962 Kraus 167-54 3,279,990 10/1966 Rose et al. 167--64 3,284,298 11/ 1966 Fujimura et al 167-65N 3,358,687 12/1967 Miley et a1 167--64 OTHER REFERENCES Unlisted Drugs, vol. 14, N0. 7, p. (July 1962). Katz et al., Jour. of Amer. Pharm. Assn. Scientific Ed. 44:7, pp. 419-323 (July 1955).
STANLEY J. FRIEDMAN, Primary Examiner
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61705867A | 1967-02-20 | 1967-02-20 |
Publications (1)
Publication Number | Publication Date |
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US3560625A true US3560625A (en) | 1971-02-02 |
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ID=24472090
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Application Number | Title | Priority Date | Filing Date |
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US617058A Expired - Lifetime US3560625A (en) | 1967-02-20 | 1967-02-20 | Method of,and formulations for,introducing alkoxybenzamides into the systemic circulatory system |
Country Status (10)
Country | Link |
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US (1) | US3560625A (en) |
AT (1) | AT277448B (en) |
BE (1) | BE711048A (en) |
DE (1) | DE1667872A1 (en) |
ES (1) | ES349148A1 (en) |
FR (1) | FR7355M (en) |
GB (1) | GB1209849A (en) |
GR (1) | GR36834B (en) |
IE (1) | IE32432B1 (en) |
NL (1) | NL6802422A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0037943A2 (en) * | 1980-03-31 | 1981-10-21 | Teijin Limited | Pharmaceutical composition for intrarectal administration, and suppository prepared therefrom |
WO2002064109A3 (en) * | 2001-02-14 | 2003-02-20 | Gw Pharma Ltd | Mucoadhesive pharmaceutical formulations |
WO2004016246A1 (en) | 2002-08-14 | 2004-02-26 | Gw Pharma Limited | Cannabinoid liquid formulations for mucosal amdinistration |
US6730330B2 (en) | 2001-02-14 | 2004-05-04 | Gw Pharma Limited | Pharmaceutical formulations |
CN1886117B (en) * | 2001-02-14 | 2014-02-26 | Gw药品有限公司 | Pharmaceutical compositions |
US10004684B2 (en) | 2001-02-14 | 2018-06-26 | Gw Pharma Limited | Pharmaceutical formulations |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU685741B2 (en) * | 1992-12-04 | 1998-01-29 | Mayor Pharmaceutical Laboratories, Inc. | Sprayable analgesic composition and method of use |
-
1967
- 1967-02-20 US US617058A patent/US3560625A/en not_active Expired - Lifetime
- 1967-11-18 GR GR670136834A patent/GR36834B/en unknown
-
1968
- 1968-01-11 ES ES349148A patent/ES349148A1/en not_active Expired
- 1968-02-07 DE DE19681667872 patent/DE1667872A1/en active Pending
- 1968-02-15 GB GB7524/68A patent/GB1209849A/en not_active Expired
- 1968-02-19 FR FR140313A patent/FR7355M/fr not_active Expired
- 1968-02-19 IE IE206/68A patent/IE32432B1/en unknown
- 1968-02-19 AT AT152468A patent/AT277448B/en not_active IP Right Cessation
- 1968-02-20 BE BE711048D patent/BE711048A/xx unknown
- 1968-02-20 NL NL6802422A patent/NL6802422A/xx unknown
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0037943A2 (en) * | 1980-03-31 | 1981-10-21 | Teijin Limited | Pharmaceutical composition for intrarectal administration, and suppository prepared therefrom |
EP0037943A3 (en) * | 1980-03-31 | 1982-12-08 | Teijin Limited | Pharmaceutical composition for intrarectal administration, and suppository prepared therefrom |
WO2002064109A3 (en) * | 2001-02-14 | 2003-02-20 | Gw Pharma Ltd | Mucoadhesive pharmaceutical formulations |
GB2388543A (en) * | 2001-02-14 | 2003-11-19 | Gw Pharma Ltd | Pharmaceutical formulations |
US6730330B2 (en) | 2001-02-14 | 2004-05-04 | Gw Pharma Limited | Pharmaceutical formulations |
KR100886668B1 (en) | 2001-02-14 | 2009-03-04 | 지더블유 파마 리미티드 | Pharmaceutical formulations |
CN1886117B (en) * | 2001-02-14 | 2014-02-26 | Gw药品有限公司 | Pharmaceutical compositions |
CZ306277B6 (en) * | 2001-02-14 | 2016-11-09 | Gw Pharma Limited | Pump-action spray formulation |
US10004684B2 (en) | 2001-02-14 | 2018-06-26 | Gw Pharma Limited | Pharmaceutical formulations |
WO2004016246A1 (en) | 2002-08-14 | 2004-02-26 | Gw Pharma Limited | Cannabinoid liquid formulations for mucosal amdinistration |
EP2314284A2 (en) | 2002-08-14 | 2011-04-27 | GW Pharma Limited | Cannabinoid liquid formulations for mucosal administration |
Also Published As
Publication number | Publication date |
---|---|
AT277448B (en) | 1969-12-29 |
ES349148A1 (en) | 1969-09-01 |
BE711048A (en) | 1968-07-01 |
IE32432L (en) | 1968-08-20 |
NL6802422A (en) | 1968-08-21 |
IE32432B1 (en) | 1973-08-08 |
DE1667872A1 (en) | 1971-07-15 |
FR7355M (en) | 1969-10-20 |
GB1209849A (en) | 1970-10-21 |
GR36834B (en) | 1969-03-15 |
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