University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 1-31-1984 Novel Method of Administering β-Blockers and Novel Dosage Forms Containing Same Anwar A. Hussain University of Kentucky Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Hussain, Anwar A., "Novel Method of Administering β-Blockers and Novel Dosage Forms Containing Same" (1984). Pharmaceutical Sciences Faculty Patents. 124. https://uknowledge.uky.edu/ps_patents/124 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Unlted States Patent [191 [11] 4,428,883 Hussain [45] Jan. 31, 1984 [54] NOVEL METHOD OF ADMINISTERING 4,012,444 3/l977 Lunts ................................. .. 424/ 324 B-BLOCKERSF0 RMS Co NTA' AND, INING NOVEL SAME DOSAGE ' 4,250,163, , 1.1’;2/l981 llieoll’loldNagaioe a ......................................... ---- -~.. .. 424/14 [7 5 ] I nventor : An war A . Hussam,° Lexington' , Ky . FOREIGN PATENT DOCUMENTS [73] Assignee: The University of Kentucky Research . Foundation’ Lexington, Ky. 979389 1/ 1965 United Klngdom . I [21] APPL Nod 241,413 OTHER PUBLICATIONS . Stern, Arzmit. Forsch, vol. 24, 1974, pp. 70-71. [22] Flled‘ Mm‘- 6’ 1981 Black, Brit. J. PharmacoL, (1965) 25, pp. 577-591. [51] Int. Cl.3 ................... .. A61K 27/00; A61K 31/15; Prima'y Examiner_stanley L Friedman A61K 31/40; A61K 31/47; A61K 31/135; Attorney, Agent, or Firm-Burns, Doane, Swecker & A61K 31/165; A61K 31/435; A61K 31/475; Mathis A61K 47/00; C07C 143/90; CllD 1/28; C09F - 5 /()() [57] ABSTRACT [52] US. Cl. .......................... .. 424/248.5l; 260/ 404.5; The invention provides a novel method of administep 260/401; 424/256; 424/258; 424/262; 424/274; ing selected known adrenergic B-receptor blocking ‘ 424/324; 424/327; 424/330; 424/358; 424/362 agents, such as dichloroisoproterenol, pronethalol, sota [58] Field of Search ..................... .. 424/ 14, 28, 34, 39, 101 and alprenolol, which are of use in the treatment of 424/230{ 24851’ 274’ 324’ 358’ 362; 260/501], angina pectoris, arrhythmias, hypertension and other 404-5 A’ 401 S’ 324’ 248'51, 262’ 256’ 258’ 327’ cardiac conditions, and migraine. The invention further 330, 274, 358, 362 provides novel dosage forms of those B-blockers which [56] References Cited an; adapted for nasal adniinistcrlatiorti andtwhich include us. PATENT DOCUMENTS so1n,ses1n,u o S s“ p n o s ge 5 an ° imn.n e 8 3,676,493 7/ 1972 Smith ......................... .. 260/4045 R 61 Claims, No Drawings 4,428,883 1 2 ride, alprenolol hydrochloride, metoprolol tartrate, NOVEL METHOD OF ADMINISTERING nadoxolol hydrochloride, pamatolol sulfate, timolol B-BLOCKERS AND NOVEL DOSAGE FORMS CONTAINING SAME maleate, bupranolol hydrochloride, etc.); generally, the selected B-blocker is employed in the instant composi BACKGROUND OF THE INVENTION tions and method in the pharmaceutically acceptable 1. Field of the Invention form which has previously been found most advanta The present invention relates to a novel method of geous for oral or intravenous use. The structural formu administering selected known adrenergic B-receptor lae for the free bases encompassed by the present inven blocking agents, and to novel dosage forms containing 10 such agents adapted for nasal administration. tion are set forth below: 2. Background Art A number of B-adrenergic blocking agents are dichloroiso- OH known. Such agents are widely used therapeutically, ' proterenol Cl | chie?y in the management of hypertension and in the 15 treatment of angina pectoris, arrhythmias and other Cl nciicmNHcmcl-mz cardiac conditions, and also possibly in the treatment of migraine. Unfortunately, however, these known B pronethalol 0H blockers are inef?ciently and variably absorbed from oral dosage forms, probably because of extensive‘ me tabolism of the drug in the gastrointestinal tract and/or extensive effects of the ?rst pass through the liver. The present inventor and his co-workers have previ ously reported that one widely used B-blocker, pro sotalol (|)H v ’ pranolol, can be effectively administered in nasal dos CHgSOgNH-Q- CHCH2NHCH(CH3)2 age form. Nasal administration of propanolol has been found to provide enhanced bioavailability and mini mized variations in blood levels as compared to oral oxprenolol 0H administration. See copending Hussain et a1.‘ Applica OCH2CHCH2NHCH(CH3)2 tion Ser. No. 063,176, ?led Aug. 3, 1979; Hussain et al. J. Pharm. Sci., Vol. 68, No. 8, September, 1979, page OCH2CH=CH2 1196; Hussain et al, J. Pharm. Sci, Vol. 69, No. 10, October, 1980, page 1240; Hussain et al, J. Pharm. Sci, Vol. 69, No. 12, December, 1980, pages 1411-1413. pindolol Iii 35 N SUMMARY OF THE INVENTION Surprisingly, the present inventor has now found that yet other adrenergic B-receptor blocking agents can be effectively administered nasally. More speci?cally, the present inventor has found that selected B-blockers, 40 OCH2(‘:HCH2NHCH(CH3)2 which differ substantially in chemical structure from OH propanolol and which also have signi?cantly different biological pro?les [e.g., they may differ in potency, metoprolol I B-blocker receptor selectivity (B1 versus 3;), agonist cmocmcm-Q-ocr-lzcncnzNncmcnm properties and/ or membrane-stabilization activity] from OH that of propanolol, can nevertheless be advantageously formulated into novel nasal dosage forms and adminis nadoxolol , OH tered nasally to provide enhanced bioavailability and | /NH2 minimized variations in blood levels as compared to OCl-I2CHCH2C\ oral dosage forms of those B-blockers, while at the same . \Non time providing relative ease of administration when compared to the intravenous route. The novel nasal dosage forms of the invention can be solutions, suspen practolol (IJH sions, ointments or gels adapted for nasal administra tion. 55 (Cl-I3)2CHNHCH2CHCH20—©—NI-I?CH; DETAILED DESCRIPTION OF THE O INVENTION butoxamine CH3 The selected B-blockers for use in the compositions HOCHCHNI-IC(CH3)3 and methods of the present invention are dichloroiso 60 proterenol (DCI), pronethalol, sotalol, oxprenolol, pin OCH3 dolol, metoprolol, nadoxolol, practolol, butoxamine, alprenolol, metalol, nifenalol, acebutolol, atenolol, CH3O bunolol, carteolol, labetalol, pamatolol, timolol, ti alprenolol prenolol, xipranolol and bupranolol. Any pharmaceuti 65 cally acceptable form of these B-blockers can be em ployed, i.e. the free base ora pharmaceutically accept OH able salt or ester thereof (e.g., oxprenolol hydrochlo 4,428,883 3 4 -continued -continued xipranolol metalol OH CH3 CH(|3HNHCH3 ' 5 H1? CH3 OH SOZCH3 ocmcncnmncmcm); nifenalol (IJH ’ i 10 O2N—©—CHCH1NHCH(CH3)2 CH3 acebutolol . bupranolol H3O cocn; l5 CH3CH2CH2CONH OCH7_(l3HCH2Nl-ICH(CH3)2 0H ' 20 These B-blockers can be made by well-known methods. atenolol (‘H-I In accord with the present invention, the selected 0CH1CHCH2NHCH(CH3)2 ,B-blockers named supra can be administered nasally with results considerably superior to those obtained with oral administration in terms of enhanced drug 25 bioavailability and minimization of blood level varia CHZCONHZ tions, thus enabling use of these B-blockers at lower dosage levels than was previously possible except in the bunolol (|)l-_l case of intravenous administration. It would appear that these selected B-blockers are rapidly absorbed from the CED-ocmcncnmnqc?a); 30 nasal mucosa into systemic blood without ?rst-pass ll ' ‘ metabolism. > 0 Any of the selected B-blockers identi?ed above can be conveniently administered nasally to warm-blooded carteolol H animals by formulating it into a nasal dosage form com I 35 prising the desired B-blocker, in an effective B-blocking N ¢O amount, together with a nontoxic pharmaceutically acceptable nasal carrier therefor. As indicated earlier, the B-blocker can be employed in the form of the free base or in the form of a pharmaceutically acceptable salt 0CH2CHCH2NHC(CH3)3 40 or ester thereof. Suitable nontoxic pharmaceutically OH acceptable nasal carriers will be apparent to those skilled in the art of nasal pharmaceutical formulations. labetalol CoNm For those not skilled in the art, reference is made to the text entitled “REMINGTON’S PHARMACEUTI OH 45 CAL SCIENCES”, 14th edition, 1970. Obviously, the choice of suitable carriers will depend on the exact U-cmcmanmtcmancit; 0H nature of the particular nasal dosage form desired, e.g., whether the B-blocker is to be formulated into a nasal pamatolol OCH2CHCH2NHCH(CH3)2 50 solution (for use as drops or as a spray), a nasal suspen sion, a nasal ointment or a nasal gel. Preferred nasal OH dosage forms are solutions, suspensions and gels, which contain a major amount of water (preferably puri?ed CHgCI-IgNHCOOCI-Ig water) in addition to the active ingredient. Minor 55 amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), emulsi?ers or dispersing agents, timolol S N/ \N OH buffering agents, preservatives, wetting agents and jell I ing agents (e.g., methylcellulose) may also be present. / \ )I——-H—OCH2CHCH2NHC(CH3)3 Most preferably, the nasal composition is isotonic, i».e. it O N 60 has the same osmotic pressure as blood serum; If de sired, sustained release nasal compositions,‘ e.g. sus~ tained release gels, can be readily prepared, preferably by employingthe desired‘ B-blocker in 'one of its rela tiprenolol OH tively insoluble forms, such as the free base or an insolu? OCHZCHCHZNHCKKCHQZ ' ‘ 65 ble salt.v When the free base is not suf?ciently insoluble for sustained release compositions, or when a more : is-cn; highly insoluble form is desired, a long chain carboxylic acid salt of the desired B-blocker can be conveniently 4,428,883 5 6 employed.