United States Patent (19) (11) 4,232,002 Nogrady 45) Nov. 4, 1980 (54) PROCEDURES AND PHARMACEUTICAL (56) References Cited PRODUCTS FOR USE IN THE PUBLICATIONS ADMINISTRATION OF ANTHISTAMINES American Hospital Formulary Service, 1966, 4:00 Anti (75. Inventor: Stephen G. Nogrady, Sully, near histamine Drugs, Penarth, Great Britain Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Young & Thompson 73) Assignee: The Welsh National School of Medicine, Penarth, Great Britain 57 ABSTRACT An antihistamine of the benzhydrylether, alkylamine, or (21) Appl. No.: 965,171 benzocyloheptatiophene class is suitable for use in the therapeutic treatment or prophylaxis of reversible air (22 Filed: Nov.30, 1978 ways obstruction by inhalation. The antihistamine may be clemastine, chlorpheniramine or ketotifen and may (30) Foreign Application Priority Data be in the form of a composition in admixture with a diluent. The antihistamine can be administered from a Dec. 1, 1977 GB) United Kingdom ..................... 5.0020 pharmaceutical inhalation device which is designed to 51 Int. Cl. ......................... A61L 9/04; A61 K9/04; administer a dosage unit of the antihistamine. The inha A61K 31/44 lation device can be in the form of a pressurized aerosol 52 U.S. C. ........................................ 424/45; 424/46; inhaler or a dry powder insufflator. 424/263 58) Field of Search ............................ 424/263, 46, 45 5 Claims, No Drawings 4,232,002 1. 2 inhalation provides the equivalent of 0.1 to 5 mg. of PROCEDURES AND PHARMACEUTICAL clemastine, or 0.05 to 2.5 mg. of chlorpheniramine. The PRODUCTS FOR USE IN THE ADMINISTRATION drug may be inhaled in the form of a mist or nebulized OF ANTHISTAMINES spray, or as a cloud of fine solid particles, and may be inhaled from a variety of inhaler devices. For example, The present invention relates to methods, and phar the inhaler device may be in the form of a pressurised maceutical preparations or charges intended for use in canister inhaler containing a propellant gas together the treatment, by inhalation, of reversible airways ob with the active drug, and having an automatic volumet struction, as for example, in asthma, chronic bronchitis, ric dosage meter to determine the volume and hence the and allergic conditions commonly known as hay fever. 10 quantity of drug administered on each actuation of the The invention is particularly valuable in cases where inhaler. Alternatively, the inhaler device may be in the rapid relief is desired. form of a portable dry powder insufflator containing a The role of histamine in the mediation of bronchial prepared capsule containing a measured quantity of the asthma is controversial. Histamine has been shown to be drug. The drug may also be inhaled as an aerosol gener released, along with other mediators, from the lungs of 15 guinea pigs previously sensitized by allergen exposure, ated in a nebulizer device driven by compressed air or upon re-challenge with the same allergen. The injection Oxygen. of histamine in some animals provokes an anaphylactoid The inhaler device may be designed to administer a reaction which includes severe broncho-spasm. In man, predetermined dosage unit of the drug, i.e. 0.1 to 5 mg the injection of histamine, or its inhalation has various 20 of clemastine, or 0.05 to 2.5 mg of chlorpheniramine. effects. In normal subjects quite large doses can be In a further form, the device consists of an insufflator, tolerated with only mild visceral effects (rapid pulse, comprising a tube having a mouthpiece, an air inlet, a abdominal discomfort, headache, and flushing). How turbo-mixer (a device for inserting the powder into the ever, in patients with asthma, chronic bronchitis, and air stream), and a means of receiving and cutting or hay fever, even very small doses of histamine, either by 25 piercing a capsule containing a dry powder including injection or aerosol inhalation, excite intense broncho the antihistamine drug. constriction. Finally, it has been shown that blood hista The device may also be in the form of a pressurised mine levels are higher in asthmatics than in non aerosol inhaler, comprising a canister containing a pro astmatic subjects, and rise significantly following aller pellant gas combined with a solution or suspension of gen induced bronchoconstriction, and in spontaneously 30 the drug and a dispensing-metering valve for dispensing occurring attacks. Sputum histamine levels are also predetermined volumes of the contents, the metered elevated in patients with chronic bronchitis in exacerba volume and the strength of the solution or suspension in tion. the container being such as to provide the required These studies suggested that antihistamines might dosage. have a place in the blocking and treatment of exacerba 35 For convenience of use, the drug may be packaged in tions of these conditions. However, numerous studies the form of a capsule containing a dry powder dose for have failed to show any significant benefit from antihis use in an insufflator, the capsule containing a mixture of tamine given orally, or by injection, in doses tolerable in the antihistamine and an inert dry powder micronised the patient. filler. It has now been found that useful effects may be For use in a nebulizer device, either as a pressurised obtained by direct inhalation of specific classes of anti aerosol inhaler or as an oxygen or compressed air histamines. driven device, the drug would normally be provided as Broadly stated, from one aspect the invention consists a solution or suspension having suitable viscosity, sur in a pharmacuetical composition for use in the therapeu face tension, and other properties for direct local appli tic treatment or prophylaxis of reversible airways ob 45 cation to the bronchi. A suitable viscosity is between 5 struction by inhalation, containing as an active ingredi and 40 centipoise. The ingredients of the solution or ent an antihistamine of the benzhydrylether, alkylamine suspension may include some, or all, of the following: or benzocycloheptathiphene class in admixture with a (a) The active agent. diluent. (b) Water, saline or ethanol (to make the solution). The composition may be in the form of a nebuliser 50 (c) Stabiliser such as Propylene glycol. (See below) solution, liquid suspension or dry powder. (d) Preservatives. The preferred antihistamines are clemastine and (e) Surface active agents ("wetting agents') to aid chlorpheniramine, preferably in the form of fatty acid droplet formation and stability. salts, the chlorpheniramine salts being derived from (f) Emulsifying agents, e.g. soya bean, lecethin or fatty acids having from 1 to 6 carbon atoms. 55 oleic acid. There is also provided, according to the invention, a (g) Antioxidants. method for the treatment or prophylaxis of reversible (h) Flavourings. airways obstruction, by inhalation of an antihistamine of the benzhydrylether or alkylamine class. (i) Buffer Solution. Preferably clemastine, which belongs to the Benzhy 60 An example of a nebulizer solution or suspension is as drylether class, is in the form of the hydrogen fumerate follows: of 1 (Methyl. 2 2-Methyl-p-chlordiphenyl methylox y)ethyl pyrolidin. Chlorpheniramine, preferably as the Clemastine 0.001 g maleate salt, is in the alkylamine class which also in Fumaric acid 0.0034g cludes Brompheniramine Maleate. Sorbitol 0.045g 65 Ethanol (94% w/w) 0.07 g The dosage, i.e. the effective quantity of the antihista Propylene glycol 0.3g mine drug inhaled at each inhalation, can be critical and Tribasic sodium according to a preferred feature of the invention each citrate dihydrate to pH 6.3 4,232,002. 3 4. -continued chlorpheniramine the solution strength will be 0.05 to 2.5 mgm/ml with an ideal solution around 0.5 mg/ml. Water to 1.027 g = 1 mi. For a pressurised "aerosol' canister inhaler the strength of the solution or suspension should be related The above corresponds to a 0.1% solution which is to the automatic metering dispenser to provide the re diluted with normal saline to produce a 0.05% solution. quired dose for inhalation. For clemastine the dose is This is then placed in a nebulizer. preferably in the range 0.1 to 0.5 mg, and with chlor An alternative method of inhalation is by means of a pheniramine 0.05 to 2.5 mg. It is anticipated that nor pressurised canister or so-called aerosol dispenser. Such mally one to two actuations will be recommended for canisters are commercially available fitted with auto 10 each inhalation and on this basis the strength of the matic metering dispensing valves designed to discharge solution can be calculated. Up to four actuations may, a predetermined volume of the contents on each pres however, be acceptable. sure actuation. Examples are given in British Pat. Nos. For dry powder inhalation the preferred clemastine 830,427 and 994,755 of Riker Laboratories Inc. dose is 0.1 to 6 mg, and for chlorpheniramine 0.05 to 2.5 Pressurised canisters of this type are charged with a 15 mixture of the active ingredient with a propellant agent, mg. In each case the dose is made up with dry pow usually a mixture of propellant gases. Such gases are dered lactose or similar filler to a suitable volume for well-known and the principal halogenated hydrocarbon insufflation from the capsule. In use the capsule is fitted gases have been provided with an international indexing in a portable insufflator provided with a device for system. The principal gases used for medical applica puncturing the capsule and a small turbo-mixer which tions are: creates a dispersed cloud when the patient inhales C11-trichlorofluoromethane through the mouthpiece. C12-dichlorofluoromethane The following examples illustrate the invention in C114-dichlorotetrafluoroethane more detail: The liquid contents of the canister may also include some or all of the further ingredients mentioned above 25 EXAMPLE 1 for a nebulizer solution.