RENIN INHIBITORS AND METHODS FOR USING SAME

Abstract: The rise in intraocular pressure associated with the use of steroidal anti-inflammatory drugs is controlled by use of a renin inhibitor.

Description: RENIN INHIBITORS AND METHODS FOR USING SAMS Glaucoma is an ocular disease complex associated with an elevated pressure within the eye (i.e., intraocular pressure, IOP). As a result of the elevated IOP, damage to the optic nerve resulting in irreversible loss of visual function may ensue. Untreated, this condition may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve damage or characteristic qlaucomatous visual field loss, is now believed by the majority of ophthalmologists to represent the earliest phase in the onset of qlaucoma. A number of the druqs presently employed to treat glaucoma are not entirely satisfactory, particularly in the earliest course of the disease when the side effects they produce are often worse than the symptoms of the disease. Epinephrine, used as a topical solution, must be utilized cautiously in patients with high blood pressure, diabetes, hyperthyroidism and cerebral artereosclerosis due to the possibility of systemic action. Timolol, a clinically utilized, topically applied aqent for lowering intraocular pressure, must be used with caution in patients in whom beta-adrenerqic blockade may be undesirable. Systemic absorption of topically administered timolol and systemic beta-blockade are responsible for the contraindication of timolol therapy for glaucoma in patients with compromised pulmonary function and in patients who cannot tolerate its systemic cardiovascular action. Pilocarpine, a topical drug, although considered systemically harmless and quite effective, may cause considerable local difficulties. Pupillary constriction . causes the eye to lose its ability to adapt from light to dark. Accommodation may become stimulated so that the patient's refraction is sometimes incorrect and vision becomes blurred. The druq itself may cause a local vasodilation and red eyes. Irritation is common. Carbonic anhydrase inhibitors have been used systemically but they have a number of disadvantages. While effective in lowerinq intraocular pressure, they often cause a numbness and tingling, gastrointestinal upsets and, frequently, depression, letharqy, a loss of appetite, and general malaise. European Patent Application 81400326.5, Publication number 36,351 attempts to overcome these difficulties by the topical administration of an alkali metal salt of a carbonic anhydrase inhibitor. The present invention is directed at the use of a renin inhibitor for the manufacture of a medicament for reducing and/or controlling excessive intraocular pressure. The present invention also is directed at the- use of a renin inhibitor in combination with a beta adrenerqic blockinq aqent and/or an anti-inflammatory steroid. The present invention also is directed at a kit comprising in separate containers in a single package a renin inhibitor in a topical opthamological carrier and a steroid in a pharmaceutically acceptable carrier. The present invention also is directed at a pharmaceutical composition suitable for treating the rise in pressure associated with the use of steroidal anti- inflammatory aqents comprisinq a renin inhibitor and a pharmaceutically acceptable carrier. Examples of renin inhibitors include, but are not limited to, the following substances, which are disclosed in the indicated publications: Reference Citing Renin Inhibitor Renin Inhibition Iva Hia Pro Fhe His Sta Leu Phβ Hypertension 6 (Suppl I): 1-111, 1984 " Pepstatin Science 175: 656, 1972 2- [ 4- ( 4 ' -chlorophenoxy ) - J Eharm Exp. Ther. 203: phenoxyacetyl -amino ] ethyl- 485, 1977 phosphoryl ethanolamine (PE 104) CH 2 CH(CH 3 ) 2 1-1-D-His Pro Phe His-NH-α.-CH 2 -Leu- Hypertension _4_ (Suppl II) : Val Tyr 11-59, 1982 Cys His Pro Phe His Cys Leu Val Tyr Ser Biochem. J. 205: 43, 1982 Lys Cys His Pro Phe His Cys Leu Val- Tyr Ser i r— Cys His ..ro Phe His C s Leu Val Tyr Lys Reference Citing Renin Inhibitor Lys Cys His ftro Phe His Cys Val Ile- Biochem. J. 205: 43,1982 His Ser Pro His Pro Phe His Phe Phe Val tyr lys Biochem. Biophys. Res. Cbmmun. 91( 1) : 230, 1980 Z-His Pro Phe His Leucinal Biochem. Biophys. Res. Corrmun. (Benzyloxycarbonyl equals Z) 118( 3) : 929, 1984 Z-Pro Fhe His Leucinal Z-Phe His Leucinal Z-His Leucinal Z-[3-{1'-naphthyl)Ala]His Leucinal His Pro Phe His D-Leu Leu Val Tyr Biochemistry 12: 3877, 1973 As Arg Val lyr He His ϊ_ro Phe His- Biochem. Biophys.- Res". G_>rπmun.- Leu Leu. Val Tyr Ser _54_: 1365, 1973 Pro His Pro Phe His Ehe Phe Val Tyr Biochemistry _14_: 3892, 1975 D-His Pro Phe His Leu 11 * Leu Val Tyr Hypertension _ (Suppl II) : 11-59, 1982 Boc-His Pro Phe His Sta Leu Phe Nature 303: 81, 1983 Pro His Pro Phe His Leu R * Val He His Lys Nature 299 : 555, 1982 Iva His Pro Phe His Sta He Phe Nature 303: 81 , 1983 Boc Phe His Sta Ala Sta Peptides: Structure^ and Function, ed V.J. Hruby , Rockford, Illinois, Pierce Chemical Co. , 1984 Arg He Pro-Ce Proc. Natl. Acad. Sci. USA 81: 48 , 1984 Boc-Leu Lys Lys Met Pro-OMe Proc. Natl. Acad. Sci. USA 81: 48, 1984 * R indicates reduction of the amide carbonyl to a methylene uni t . Reference Citing Renin Inhibitor Renin Inhibition Boc-Arg He Pro Leu Lys Lys Met Irto-OMe Proc. Natl. Acad. Sci. USA _§ 48 , 1984 Boc-Glu Arg He Pro Leu Lys Lys Met Pro-OMe Ac Val Val Sta Ala Sta Iva Val Val Sta Ala Sta Glu L- -hydroxy-isocaproyl-Leu Val Phe-CMe Biochem. Biophys. Res. Commu 100: ( 1) 177, 1981 L-α-hydroxyisovaleryl Leu Phe-OMe L-α-hydroxy ' isovaleryl Leu Val Phe-OMe L-α-hydroxyisovaleryl Leu Val Phe(N0 2 ) -CMe L-α-hydroxy-isovaleryl Leu Val Tyr(Me)-CMe . L-α-hydroxy-isovaleryl Leu Val Phe(NH 2 )-OMe Lac Leu Val Phe(N0 2 )-0Me lac Leu Val Tyr(Me)-0Me Lac Leu Val Phe(NH 2 )-OMe H-Leu Val Phe(NO 2 )-0Me H-Leu Val iyr(Me)-CMe Heparin J. Clin. Endocrinol. _27_: 69 Deoxycholic acid Biochem. Pharmacol. 20 % 914 Phosphotidyl ethanolamine Proc. Soc. Exp. Biol. Med. where acid substituents thereof are each 1977 independently arachi onic acid, linolenic acid or stearic acid -6- Reference Citing Renin Inhibitor Renin Inhibition Capric acid . J. Physiol. 234(6): E 593, Laurie acid Palmitoleic acid Linoleic acid Arachidonic acid N-Ac Ile-OCH 3 Biochemistry 19: 2616, 1980 N 2 Ac Leu-CCH 3 1,.2-epoxy-3-(.p-nitrophenoxy)propane Sta Leu Phe Nature 303: 81, 1983 His Sta Leu Fhe Phe His Sta Leu Phe Pro Phe His Sta Leu Phe Ibu His Pro Phe His Sta Ibu His Pro Phe His Sta Leu Ibu His Pro Phe His Sta Leu Fhe Ibu His Pro Phe His Sta Ala Phe Ibu His Pro Phe His Sta Val Phe Ibu His Pro Phe His Sta He Phe Boc His Pro Phe His Sta Leu Tyr Boc His Pro Phe His Sta Leu Phe-0CH 3 Iva His Pro Phe His Sta Leu Val Phe POA Leu Sta Val Phe-OCH 3 (PCA equals phenoxyacetyl) POA Leu Sta Leu Fhe-CCH 3 -7- Reference Citing Renin Inhibitor Renin Inhibition POA His Sta Leu Phe-OCH 3 Nature 303: 81, 1983 Iva His Efco Phe His Leu Sta Val Phe Iva His Pro Phe His Sta Leu Phe Boc-Phe Phe Sta BmSta-NH J. Chem. Soc. Chem. Cbmmun: 109, 1985 Naphthylalanyl His Sta-4-amino-l-benzyl Kokubu et al.. Hypertension: piperidine 1( 3) 837 (1985) BNMA His Sta-2(S) -methyl butylamine " BNMA Val Sta Isoleucinal " 2,3-naphthylalanyl Leu Sta Isoleucinal " BNMA Norleucinyl Isoleucinal " Another class of ren in inhibi tors are compounds of the formula wherein R la is selected from cyclohexylmethyl , benzyl or butyl; X a is S or 0; R 2a is selected from isobutyl, cyclohexylmethyl or benzyl; and R 3a is phenethyl. A preferred compound within this class is one wherein R la is cyclohexylmethyl, R 2a is isobutyl, R 3a is phenethyl and X a is S. These compounds are described by Luly et al.. Pharmacologist _27.(3) : 260 ' 1985, and can be prepared by known techniques from known materials. BNMA=beta-naphthyl methyl analyl Other renin inhibits are disclosed, for example in Szelke et al. U.S. Patent No. 4,424,207 discloses as having the formula X-Y^-Pro-Phe-Hi. A^— B-Z-W 00 6 7 8 9 10.11 12 13 where Pro, Phe and His may be in substituted form; X^=H; or an acyl or other N-protecting group e.g. acetyl, pivaloyl.l'bυjyloxycarboπyl (Boc), benzoyl or lower aJkyl (primarily C1-C5); or an L- or D- amiπo-acyl residue, which may itself be N- protected similarly; Y {==DD-- oorr LL--HHiiss oorr ooottthi er D- or L- basic or aromatic amino-acεtyl rreessiidduuee, or is absent; Ri fe R 2* o (VIII) I I ^ — NH— CH— CH(OH)— CHj— CH— C "hydroxy" \ isostere bond where the configuration at asymmetric centres * is either R or S, where in VIII the hydroxy group may be present as such or protected in ether — OR >r ester — o— c * form where R^is as given under W oelow and where R^and R 2 the same or different='Pro (iso- propyl), ' u (isobutyl), Bzl (benzyl) or other lipo- philic or aromatic amino-acid side chain R 3 -_— H; lower alkyl (Cj-Cj); or — S0 2 Ph, — Sθ 2 <-_H_tCH 3 (p), Boc, formyl or other N- protecting group; B'-.D- or L- Val or He or other D- or L- lipophilic aminoacyl residue; Z^D- or L- Tyr, Phe, His or other L- or D- aromatic aminoacyl residue; and o — c \ CH 2 - hydroxy, — CH(OH) — CH 2 — , or hydrocarbon, — CH- 2 — CH 2 — isosteric links and further being in free form or in protected or salt form at one or more remaining peptide, carboxyl, amino, hydroxy or other reactive groups, in particular as their physiologically acceptable acid addition salts at basic centres. Veber et al. U.S. Patent No. 4,479,941 discloses as renin inhibitors compounds of the formula wherein: ^is hydrogen; O O RA-O— C— : or -t^CHtfuC-C— where ιήs 0 to 5 and R'fcai the same meaning as set out further below, and may additionally be hydro* gen; ΕHa absent; glycyl; sarcosyl; or R ιc — N £' C— : I II H O u is absent; or where 2fn ' (CHj)* and n5is 1 or 2; or — S — ; RΗs hydrogen; C1-4 alkyl; hydroxy C alkyl; phenyi; phenyi mono-substituted with a member selected from the group consisting of methyl, tri- fluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; -im.da2olyl; amine C2-* alkyl; guanidyl Cj aikyl; or methylthiomethyi; R^s hydrogen Cι_ι; alkyl; phenyi; phenyi mono-sub¬ stituted with a member selected from the group consisting of methyl, tπ luoromethyi, hydroxy, methoxy, fiuoro, chloro, bromo, and iodo; or indo¬ lyl; R J4 is CM alkyl; C3.7 cycloalkyl; phenyi; or C3-τcy- cloaikyl or phenyi mono-substituted with a mem¬ ber selected from the group consisting of methyl, trifluororaβthyl. hydroxy, methoxy, fluoro, chloro, bromo. and iodo; R*_ι hydrogen; or where R*_ι hydrogen; Ci-* alkyl hydroxy; or C3.7 cycloalkyl; and where Y — NH— or - — ; n_i» 0 to 5; and R*-. hydrogen; hydroxy; Ci-αlkyi; C3.-cyci0a.kyi; aryl; aryl tubatituted with up to five members independently selected from the group comating of Ci^alkyl, trifluoromethyl. hydroxy, Ci-αlkoxy, amino, mono- or di- CM alkylamino, and halo; amino; mono-, di-, or tri- Ci-vaikylamino guanidyi; heterocyciic; or heter- ocyclic substituted with up to five members in¬ dependently selected from the group consisting of Ci- lkyl, hydroxy. trifluoromethyl; Ci._ta.k- oxy, halo, aryi, aryl Ct-taikyl, amino, and mono- or di-Ci-talkylam-Oo; where YTS as defined above; ■ n.is 0 or I; kώ 0 or I; leis 1 to 4; tnis 1 to 4; and R*tnd R**may be the same or different and have the same meaning as ^bove and R«*tnay addi¬ tionally be o o C 11 R 7 ..*. or C » N OR 74, I H where R*is hydrogen or Ci alkyl; or where Yπs as defined above; neis 0 or 1; and Z*is (i) -(CHtf^-CH- where rcis 0 or t; and R*is as defined above; or (b ) -(CHΛT?"* CHj where ntis 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E sub¬ stituents, which may have an S or R coniguraαon; and a pharmaceutically acceptable salt thereof. Compounds within the class include IBU 1 — His-Pro-Phe-His-Sta-Leu-benzyiamiαe: IBU— His-Pro-Phe-His-S -Leu-2.phenylethyiamide; IBU— His-Pro-Phe-His-Sta-L β u -phenylpropyla- mide; IBU— His-Pro-Phe-His-Sta-Leu-1.2-diphenyiethy la¬ mide; BOC-— Phe-Hi3-S -Leu-(-r-) J -1.2-diphenyiethyla- mide; BOC— Phe-His-S -Leu-(-)- l.2-diphen leth . !a- rπide; BOC— Phe-His-Sta- Leu-beπzy lamide: BOC— Phe-His-S.a-Leu-< I- .-α-pheπy lethylamide: BOC— Phe-His-Sta-Leu-( - )-α-phenyIethyIamιdβ: BOC— Phe-His-Su- eu-< + )-α-naphthy lethyla- ide; BOC— Phe-His-Sα-Leu-<-)- -naphthylethy la¬ mide; BOC— Phe-His-Sta-Leu-p-chlorobenzy lamide: BOC— Phe-His-S -Leu-p-methoxyenzyiamide; BOC— Phe-His-Sta-Leu- 10.11 -dihydro-5H-diben- zo(a,d]<ycloheρteneamide BOC— Phe-His-S -Leu-D,L-threo-l,2-diphenyl- 2-hydroxyethyIamide; BOC— Phe-His-Sta-Leu-Sta; BOC— Phe-His-AHPPA*-Lleu-benzylamide Acetyl— Phe-His-AHPPA-Leu-benzyiam.de; BOC— Phe-His-S -Leu-(2-amidomethylpyridine); BOC— Phe-His-Sta-Leu-{4-_midomethylpyπdine); BOC— Phe-His-Sta-Leu-(4-_mιdo- l-benzylpiperi- diπe); BOC— Phe-His-Sta-Leu-{N-{3-__n.dopropyl)die- thanoiaminej; BOC— Phe-His-AHPPA-Leu-Oamidomethyl- pyridine); BOC— Phe-His-ACHPA le-<2-amidomethylpyri- dine); IVA 6 -His-D-Pro-Phe-His-ACHPA-Ile-{2-amidome- thylpyridine). 'IBU-iIso-butyryl. ' BOC =» Teπ-buiylo-ycarbonyl. '( -- ) refers to the optical rotation of the amine. ΑHPPA-.-S. S)-*«ιmuιo-J._y roιy-5.pheaylpeι.t_ao-: acid. 5 ACHPA_ι(3S. -S)^unuιo-5-cyclo-€»yl-3-hy-ro»yp«_ti-_oιc tad. s IVA -.(so-valeryi. A preferred compound within this class is BOC-Phe-His- Sta-Leu- (4-amido-l-benzyl-piperidine) . Veber et al. U.S. Patent No. 4,478,826 discloses as renin inhibitors- compounds of the formula wherein: A" is hydrogen; where nαs 0 to 5 and ^has the same meaning as set ut further below, and may additionally be hydrogen; Eris absent; glycyl; sarcosyl; or A absent; or 1 o where iris (CH_).d_nd n4 1 or 2; or —5—; R' s hydrogen; CM aikyl; hydroxy C alkyl; phenyi; phenyi mono-substituted with a member selected from the group consisting of methyl, trifluoromethyi, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C2- alkyl; guamdyl C2-3 alkyl; or methylthiomethyl; ^is hydrogen C1- ; aikyi; phenyi; phenyi mono-sub¬ stituted with a member selected from the group con¬ sisting of methyl, trifluoromethyi, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; ^is C3-* alkyl; C3-7 cycloalkyl; phenyi; or phenyi mono-substituted with a member selected from the CH-R where R^s hydrogen; CM alkyl; hydroxy; or C3-7 cycloalkyl; and . Is is OϊC; NHIC * or N(lQ 2 , where each IT may be the same or different and is hydrogen or C M aikyl; wherein ail of the asymmetric carbon atoms have an S configuration, except those of substituents ETand Ol which may also have the R configuration; and a phar¬ maceutically acceptable salt thereof. Examples of compounds within the class are His-Pro-Phe-His-Su-Leu-Phe-NHj, iso-Valeryl-His-Pro-Phe-His-Stt-Leu-Phe-NHj, Acetyl-Pro-Phe-His-Stt-Leu-Phe-NH:, Acetyl-Phe-His-Sta-Leu-Phe-NH., tert-Butyloxycarbonyl-Phe-His-Sta-Leu-Phe-NH2. tert-Butyioxycarbony.-His-Pro-Phe-Phe-Sta-Leu-Phe- Hi iso-Butyryl-His-Pro-Phe-His-Sta-Ala-Phe-NH:, Cyclo. i_ Butyryl-Ha— Pro— Phe— Ha— Sta { hexyl-Phe— NHj ( AU - A preferred compound within this class is IVA His Pro Phe His Sta Leu Phe-NH - Renin inhibitory activity is disclosed in Veber et al. U.S. Patent No. 4,384,994 for compounds of the formula wherein: -*As hydrogen; or pbenoxyacstyi R*is C« straight or branched alkyl; Cj.7 cycloalkyl; phenyi; or phenyi mono-substituted with hydroxyl, fluoro, chloro, bromo, methyl, or trifluoromethyi; R^s hydrogen; or methyl; R^ζs methyl; or isopropy R* 6 ^ phenyi; or 4-hydroxyphenyi; and I^ts Ofq NH_β or NI where each Ffma be the same or different and is hydrogen or C 1 -4 alkyl; and a pharmaceutically acceptable salt thereof: all of the asymmetric caroon atoms having an S coαfiςurction. Exemplary are N-phenoxyacstyl-L-leucyK3S.4S>statyl-L-valyl-L- phenylalaaine; N-phenoxyacetyi-L-leucyK3S,4S «tttyl-L-leucyl.L- phenylalantne N-phenoxyacetyl-L-!eucyl-4(S amino-3(S>hydroxy-5- phenylpentanoyl-L-leucyl-L-phenylalaπine; L-leucyl-(3S,4S>_iatyl-L-v_lyI-L-phenylalaπine; L-leucyW3SΛS>-statyl-L-leucyl-L-phenylaian_.e; L-ieucyi-* ( S>-amino-3(S)-hydroxy-5-phenyl?entanoyl- -leucyl-L-phenylalanine; and the amide and CM alkyl ester forms of the above peptide. Boger et al. U.S. Patent No. 4,485,099 disclose compounds having renin inhibitory activity of the formula wherein: A*is hydrogen; or where. X r is -O— : -0— CH— : — CH— O— : 1 1 -CH— . -NH-CH-: or -S-CH-: and C3-7cyc.oa.kyl or aryl substituted with up to five members independently selected from the group consisting of Ci-jalkyl. trifluoromethyi. hy¬ droxy, C|._taikoxy, and halo; pris 0 to 5; and p'rand p' are independently 0 to 2; except that where XTis — O— , only one of R_>%r Ri'is present; ff is absent; glycyl; sarcosyl; or where R* S hydrogen; C M alkyl; hydroxy Ci... alkyl; aryl; aryl substituted with up to three mem¬ bers selected from the group consisting of Cι -al¬ kyl, trifluoromethyi, hydroxy, Cι_ul o*y, and; halo; indolyl; 4-imιdazolyl; amino -taikyi; guant- dyl C2.3 alkyl; or methylthiomethyl; O is absent; or where Z s — <CH_)ιf- and Ifis 1 or 2; or — S— ; E is absent; or I CHi — N A • C— I II H 0 where R*ns hydrogen; Ci-αlkyl: aryl; aryl Ci-aal- kyl; or aryl Cι-udkyi or aryl where the aryl portion is substituted with up to three members selected from the group consisting of Ci- lkyl, tπfluoro- methyl, hydroxy, Cι-4alkoxy, and halo; or indolyl; F is absent; or glycyl; R s C 3 -6 alkyl; C 3 -7 cycloalkyl; aryl; or C3-τcycloal- kyl or aryl substituted with up to three members selected from the group consisting of Ci-αlkyl. trifluoromethyi, hydroxy, Cι-4alkoxy, and halo; R 4< ϊs hydrogen; or — H— ^ Λ* r C where R 7 s hydrogen; Ci-αlkyi; hydroxy: or Cj-τ. cycloalkyl; and 6 ^s as defined above; R^s hydrogen; -CH— R 7 . wherein all of the asymmetric carbon atoms have an S configuration, except for those in the ft. Br and D r sub- stituents, which may have an S or R configuration and a pharmaceutically acceptable salt thereof. Examples of compounds wi thin this class include IBU— Hi»— Pro— Phe— ys— Su— Leu— Phe- 3 IBU ■ — Hia— Pro— Phe— Orn— Sta— Leu— Phe-η i I IBU— Hia— Pro— Phe— OAB 1 — Sta— Leu— Phe— Gly— i i I IBU— Hia— Pro— Phe— HLy* 1 — Su— __.— __D IBU— His— Pro— Phe— Orn— Su— Leu— Phe— Oly — i i 1 IBU— Hia— Pro— Phe— ys— Su— eu— Phe— Oly 3 BOC*— Phe— Lys— Su— u— Phe— » I ; I IV A 6 — His— Pro— Phe— Lys— Su— Uu— Phe 1 IVA— His— Pro— Phe— Lys— AHPPA— Uu— Phe- 1 POA— Lys— ACHPA 1 — lie— His - 3 BOC— Phe— Lys— ACHPA — lie— His • ' 3 IVA— His— O-Pro— Phe— Lys— AHPPA— u— Phe 1 IVA— His— D-Pro— Phe— Lys— ACHPA— Uu— Phe- 3 IVA— His— D-Pro— Phe— Lys— ACHPA— He— His- IBU * Ivj-βulyl. 3 : DAβ » SS— -.mino-t-umnoβtilync >cιd. 'HL. j - Ho oly«n«. IS— »mιιιo-»-«mιno_t «ι_o«c -ad. 'BOC » Ttπ- _eylo«yc_r8θΛ»l. 'AHPPA - i .S. *SM-AιτHn_.J.hyι3roιyS.ph«-yl-p«ιuno«: «n*. "IVA _ l_>-v« ryl. 'POA _ PHrø»ya___ty.. 1 ACHPA - IIS. *S)-hAmflt»S<yclolκ_yl-3-hydroιy-p« unαc act*. A preferred compound within this class is BOC Phe Cys Sta Leu Phe'. Renin inhibitory activity is disclosed in Boger et al. U.S. Patent No. 4,477,441 for compounds of the formula wherein: A lβ hydrogen; or where Jt ls — O— j -O-CH-j -CH-O-i or -CH-; and Rj 1 and Ri 1 may be the same or different and are hydrogen; γ2-(CH 2 ),i- or Y*-<CH 2 -CH= CH-^CHϊ ^ where Y»is hydrogen; Ci- 4 -Jkyl; aryl; C3.7cycloalkyl; or C3-7cycloalkyl or aryl sub¬ stituted with up to five members independently wherein R^is hydrogen; CM alkyl; hydroxy CM alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C.-talkyl, triflu¬ oromethyi, hydroxy, -ialkoxy, and halo; indolyl; 4-imidazolyl; amino C 2 _t alkyl; guanidyl C2.3 alkyl; or methylthiomethyl; D^is absent; or w a < Efis absent; or where R^s hydrogen; Ci-ialkyl; aryl; aryl Cι-*alkyl; or aryl Cι-+alkyl or. aryi where the aryl portion is substituted with up to three members selected from the group consisting of Ci-μdkyl, trifluoromethyi, hydroxy, C|_*alkoxy, and halo; or indolyl; F*!β hydrogen; — CH— 7 :' where Rπs hydrogen; C.-t-Jkyl; hydroxy; or C3-τcy- cloalkyl; and R^ as defined above; R4n hydrogen; — H— 7 ? ( of halo, di-Ci-ialk- have an S B? D and F 9 may Compounds within the above class include IBU 1 — Hit— Pro— Phe— Cyi— Su— Leu— Phe— NH -s S- 1 IBU— Hia— Pro— Phe— Hcys 1 — SU— Uu— Phe— NH— i Phenoxyacetyi-Cya— AHPPA 3 — u— Phe— N» 3 Phenoxyacetyi-Cya— ACHPA — He— H —NH 3 Phenoxyacetyi-C ;yvsa—— A ACCH) PA— He— Hia— Cy»— NH 2 IVA 3 Hia— D-Pro— Phe— Cya— ACHPA— He— Hia— NH- 3 Boger et al. U.S. Patent No. 4,477,440 discloses compounds having renin inhibitory activity of the formula wherein: A is hydrogen; or where X is — O— ; — O— CH— ; — CH— O— ; or — CH— ; I I I and Rtf' and R4 1 may be the same or different and are hydrogen; Y^- CH 2 )„— where Y*is Cι-_ι__kyl; hydro¬ gen; aryl; C 3 .7cycloalkyl; or C3-7cycloalkyl or aryl sub¬ stituted with up to five members independently selected from the group consisting of C.-galkyl, trifluoromethyi, hydroxy, Ci-μdkoxy, and halo; n*is 0 to 5; except that B 4 is absent; glycyl; sarcosyl; o -r 21- where R sl _j hydrogen; C alkyl; hydroxy CM alkyl; aryl; aryl substituted with up to three members selected from the group consisting of Ci-ialkyl, trifluoromethyi, hydroxy, Cι_4alkoxy,.and; halo; indolyl; 4-imidazolyl; amino C 2 _ . alkyl; guanidyl C2.3 alkyl; or methylthi- omethyl; Lf*. where Z is — (CH 2 )^- and p is 1 or 2; or — S— ; E is absent; or where R 6 is hydrogen; -CH-R'* where R 9i ιs hydrogen, Cι- alkyl, hydroxy, or C -7cy- cloalkyl; or — CH 2 R 10 f> where R 10 "is 4-imidazolyl, amino-C 2 - t alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C.^al- kyl; s st ng of Ci-*__ky_, trifluoromethyi, hydroxy, oxy, amino, mono- or diCi-ialkylamino, and halo; amino; mono-, di- or tri-CM-lkylamino; guanidyl; het¬ erocyclic; or heterocyclic substituted with up k h h . where Y XΆ M defined above; k is 0 or 1; k' is 0 or 1 k" is 1 to 4 k'" ιβ 1 to 4; and R 7 and Rβ iay be the same or dilTerent and have the same meaning as 7τ»*o»- -< Λ α 7A may additionally be C R 1 * C N or OR 1 h I H where R' is hydrogen or Cι._alkyl; or where Y is as defined above; r is 0 or 1; and Z is — (CHύr— CH— W __•* where r' is 0 or 1: and R 8 is as defined above: or -(CHtfA- c— W ti CH 2 i wheie r" is 0 or 1; R2ls hydrogen; Cι_»alkyl; aryl; aryl substituted with up to three members selected from the group consisting of Ci-talkyl, trifluoromethyi, hydroxy, Ci_ialkoxy, and haloj or indolyl; R^s C3-« alkyl; C3-7 cycloalkyl; aryl; or C3_7cycloal- kyl or aryl substituted with up to three members se¬ lected from the group consisting of CMalkyl, trifluoro¬ methyi, hydroxy, _ alkoxy, and halo; R 4 Ts hydrogen; or -CH-R 11 * Exemplary of compounds within this class are M Hoys 2 — Pro— Phe— Hcys—Su—Uu— Phe— OCH3 S S Cys— Pro— Phe— Cys— S — Uu— Phe— OCH3 s-l enm in tory peptides of the formula are disclosed in Boger et al. U.S. Patent No. 4,470,971 wherein: A* is hydrogen o o H • II R*-0— CH 2 -C- R 3 C H -0-C-: o o R 3k -0— C-; of R 3 MCH 2 )_.l-C-. where is 0 to _ and R 3 4_as the same meaning as set • out further below, and may additionally be hydrogen;. B is absent; glycyl; sarcosyl; or O is absent; or where Z^is (CH:),. πd tύis I or 2; or — S— ; R"-S hydrogen; CM alkyl; hydroxy CM alkyl; phenyi; phenyi mono-substituted with a member selected from the group consisting of methyl, trifluoromethyi, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C aikyl; guanidyl C 2 .3 alkyl; or methylthiomethyi; R^is hydrogen Cι-« alkyl; phenyi; phenyi mono-sub¬ stituted with a member selected from the group con¬ sisting of methyl, trifluoromethyi. hydroxy, methoxy, fluoro. chloro. bromo, and iodo; or indolyl; R 3,: is C 3 . 6 alkyl; C 3 .7 cycloalkyl; phenyi; or phenyi mono-substituted with a member selected from the group consisting of methyl, trifluoromethyi. hy¬ droxy, methoxy, fluoro, chloro, bromo, and iodo; R**is hydrogen; or CH— -.^ where R''is hydrogen; C alkyl; hydroxy; or C3-7 cycloalkyl: R*ιs 4-ιmidazolyl; amino CM alkyl; 2-, 3-, or 4-pyridyl; ,or guanidyl C2.3 alkyl: and , E. is OR'< NHR' . ' or N(R"fc, where each R"«may be the same or different and is hydrogen or CM alkyl; wherein all of the asymmetric carbon atoms have an S. configuration, except those of substituents B'and Df which may also have the R configuration; and a phar¬ maceutically acceptable salt thereof. Exempl ary ar^ 's^8»"yryl-Hi3-Pro-Phe-His-Sta-Val-His-Giy-NH 2 i so-Butyryi-His-Pro-Phe-His-Stt-Ile.His.NH 2 tert-Butyloxycarbonyl-Phe-His-Su-Ile-His-NH: Beπzyloxycarbonyl-Phe-His-Stt-Ile-His-NH: i so-Valeryl-His-Pro-Phe-His-Sta-He-His-NHj i so-Valetyl-His-Pro-Phe-His-Sta- eu-His-NH: A preferred compound within this class is IVA-His-Pro- Phe-His-Sta-Ile-His-NH 2 - Cazaubon et al. U.S. Patent No. 4,481,192 discloses renin inhibitors of the formula «?-xi-? -will At. I-> r » m in which Statyli denotes th* radical derived from th* amiaoa d statute, namely: and Statyt] denotaa the statyl radical derived from the same mimtrrid, bat can be the 3S.4S iaocaer or the R*deooeβa a hydrogen atom or an acyiating group attached to the termtnal amino group of the aminoacid More particularly, R' caa rt present the following groopβ. acetyl (Ac), iaovalβryi (iva), octyL, t-butyla- cety t-butoxycarbonyl (Boc) adamantytoxycarbonyl (Adoc), benxyloxycarbcmyl (Z), (benzytoxycarbonyl)- ^-aminoethylsulpbonyl (Z-Tau), (t-butoxycarbooyl> / 3- anuno-4 ethyisoipbooyl (Boc-Tau), phenyisulphonyi, benzytsulphqαyl or 3-phenyiproptonyl. X f and Y which are identical or different, denote aminoacids of the or O configuration when a centre of asymmetry exists in the molecule, and optionally protected in their side chain. A preferred compound within this class is BOC Phe His Sta Ala Sta-OMe. Renin inhibitors of the formula 2^fto-Plιe-H»^χ¥v_.Tτ-(t ) .).y K rø are disclosed in Haber et al. U.S. Patent No. 4,478,827 wherein His is histkϋne. Pro is proline, Phe is phenylaia- nine, Val is vaiine and Tyr is tyrosine. The X3 are the same or different and are an aromatic or aliphatic amino acid. These may be selected from the group consisting of phenyialanine, a chlorinated phenyialanine such as chiorophenylalanine, dichlorophenyialanine, tyrosine. leucine. giycine, isoleucine. vaiine or the like. Y*is a charged amino acid residue at the C-teπninus of the polypeptide which can be either positively or nega¬ tively charged including lysine, argtαine. ornithine. aspartic or glutamic acid and their α-carbon esters of lower aliphatic alcohols (Cι-C«) and their primary or secondary lower (C 1 -C 4 ) aliphatic amides. This charged amino acid residue has the effect of both ex¬ tending the half-life of the poiypeptide molecule in vivo and increasing its solubility, thereby to render the poiy¬ peptide effective in inhibiting renin in vivo. 2_*can be either proline, hydroxyproiiae, thwprohnβ or polypro* line having up to about 5 prolyl ΓTTJTIHTΓ in ι Exemplary are: pro-I-i---^o-P_ < e-Hi_-Phe-P e-Val-Tyr-D- ys pro-H__-Pro-Phe-H__.Leu-Phe(Cl>Val.Tyr-D.Ly« pro-Hi_-Pro-Phe-Hi»-Leu-Tyr-Val-Tyr-D-Lys Pro-His-Pro.Phe-H__. eu-Phe-Val-Tyr-D-Lys Hansen, Jr. et al. U.S. Patent No. 4,510,085 discloses compounds of the formula as having renin inhibitory activity wherein R'«.s: (a) hydrogen: or ( b) alkyl of I to 6 carbon atoms, inclusive: wherein R-^is: (a) hydrogen: or (b) alkyl of 1 to 6 carbon atoms, inclusive; wherein R**is: wherein R*^and R'J each being the N me or different. are: (a) hydrogen: (b) alkyl of 1 to 6 carbon atoms, inclusive: or (c) halogen: wherein fis 0. I or 2. wherein nfis 0 or n integer of from I lo 4. and the pharmaceutically acceptable alts thereof Tetrapeptide adamantyl amides are disclosed in U.S. Patent No. 4,514,332 as having renin inhibitory activity. - These compounds are of the formula wherein R"!s: (a) or (b) straight or branched chain alkyls of 1 to 6 car¬ bon atoms, inclusive; wherem R^U: (a) hydrogen: or (b) alkyl of I to 3 carton atoms, inclusive: wherem R 3 ^: (a) CH 2 C_H 5 ; or (b) alkyl of 1 to 3 carbon atoms, inclusive: wherem R*H: (a) hydrogen; or (b) aikyl of I to 6 carbon atoms, inclusive; wherein m*1s 0. 1, or 2; wherein πts I or 2; wherein jfs 0, 1. or 2; and the stereochemicai configuration of each of the optically active ammo acid residues may independently be D, L or DL; and the pharmacologically acceptable salts thereof. Burton U. S. Patent No. 4 , 455 , 303 discloses as having renin inhibitory activity compound of the formula wherein A, B, D are tint same or different amino acid residues selected from the group consisting of: Phe, Phe (4-C1). Tyr, Phe (4-0 and Tyr (orthc-Me) C is Val, Thr or threo- 3-anuno-3- hiorobutyric acid; £_*is lysine or arginine; -^is NH* OH, or OM? where M*is a physiologically acceptable cation; or addition salts of said pentapepαde. Examples of such compounds include ■ Renin inhibitors are also disclosed in Burton et al-.- U.S. Patent .No. 4,269,827 as having the formula 2?Hi»-Prβ.P>_-.HB.^Λ' J-Tyr.γ Formula 1 wherein His is histidine. Pre is proline, Phe is phenyiala¬ nine, Val is vaiine and Tyr is tyrosine. The Jα are the same or different 2nd are an aromatic or aliphatic amino acid selected from the group consisting of phenyiala¬ nine, a chlorinated phenyialanine such as chloro- phenyiaianine. dichiorophenylaianiπe, leucine. isoleu- cine, vaiine or the like or tyrosine. Y s a charged amino acid residue at the C-teπninus of the poiypeptide which can be either positively or negatively charged including lysine, arginine, ornithine or aspartic acid. This charged amino acid residue has the effect of both extending the half-life of the poiypeptide molecule in vivo and in¬ creasing the solubility thereby to render the poiypep¬ tide effective in inhibiting renin in vivo. Z^can be either proline or poiyproline having up to about 5 prolyl resi¬ dues in series. Examples are Λ_.H»Pr P _t.H».Pt»Pha.Val-Tyτ-Ly. Pn>H»I o.P_(-H»LM-αPlM>Vtl-Ty^Ly» Pπ H»Pι_-Ph^HJa-L__.Trr.V_μTyτ-l.ra i^o>H-^Prα-P1w-Hi*-L«u-PlM>Vt|.Tyr-Lys Castro et al . U. S . Patent No . 4 , 185 , 096 d isc loses compounds of the formula their salts. as having renin inhibitory activity. In the general formula (I) each of the symbols Y and Z " which are identical or different, represent an amino-acid residue selected from arginine, giutamic acid, aspsrac acid, lysine, histidiae or vaiine, forming with the free carboxyl group of the pepstaan or of the adjacent amino-acid a pepαd-j bond-CONH— ; the car¬ boxyl function of the terminal amino-acid may exist in free form or in the form of an ester of an aliphatic aico- hoi containing 1 to 4 carbon atoms, and the indices *},b^ and a/u each equal to zero or 1, the sum ajf-yr-ojbeing equal to 1, 2 or 3. Hayaski et al. U.S. Patent No. 3,985,875 discloses as having renin inhibitory activity compounds of the formula c wherem R k» an oc adeca- 0 , 1 -dienoyi, octadec*. 9,12,15-trienoyl, 4-{4'-chlorophenoxy)phenoxya- cetyi or β-{4K4'-chloropr_enoxy)p_-enoxy}propio- nyi group, and m β 2 or 3. or their pharmaceutically acceptable acid addition salts- In describing such renin inhibitors the superscript letters a-r (the letter "o" having been omitted) were included to distinguish among the various classes of compounds and the variable substituent groups therefore. It is believed that any renin inhibitor will possess the novel utility described herein; however, for purposes of the present invention the preferred renin inhibitors are compounds which are capable of inhibiting the action of renin by at least 50% at a concentration of 1 uM or less, and especially preferred renin inhibitors are compounds which are capable of inhibiting the action of renin by at least 50% at a concentration of 10 nM or less, when tested by the following standard method, which is a modification of the procedure described in Burton et al.. Biochemistry _14_:3892-3898, 1975: Hog renal renin (0.1 mU), (5-15 U/mg protein) is used to generate angiotensin I (A I) from tetradeca- peptide (TDP). (Human renin and human renin substrate or TDP may also be used). The reaction mixture also consists of 0.5 mM dimercaprol, 0.5 mM hydroxyguinolone, and 0.1 M maleate buffer, pH 6.0, containing 0.5% bovine serum albumin to bring the total volume to 250 ul. Test drugs or known renin inhibitors, e.g., pepstatin, H-108, are added in concentrations of 100 uM and lower. After 30 minutes incubation at 37°C, the tubes are boiled for 5 minutes to stop the enzyme reaction. Enzyme is added to zero time tubes after boiling. Then, 250 μL of 0.1 M maleate buffer are added to all tubes after boiling. Tubes are centrifuged for 10 minutes at 2800 rpm (1650 times g) in an IEC Centra-7R centrifuge and the supernatant solutions are decanted into clean tubes. These samples are either stored frozen at -70°C and then assayed at a later time or assayed immediately using a radioimmunoassay kit to quantify A I generated. Data are expressed % inhibition of renin. . Many renin inhibitors are known in the art and may be prepared by known methods or by variations - thereof. ' The renin inhibitors employed in the invention may exist in isomeric form. The invention contemplates all such isomers both in pure form and admixture, includinq racemic mixtures and their pharmaceutically acceptable salts. The pharmaceutical compositions of the invention are administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye; such as solutions, suspensions, ointments and solid inserts. Formulations of the invention may contain the renin inhibitor in an amount of from about 0.00001 to about 1.0 (w/v%) and especially about 0.00001 to about 0.1% of medicament. As a unit dosage form, an amount of renin inhibitor from between about 5 ng to about 0.5 q, preferably 5 ng to 50 ng of the active substance is applied to the human eye. Where utilized herein, the term "controlling the elevated intraocular pressure" means the regulation, attenuation and modulation of increased intraocular tension, which is the primary diagnostic symptom of the disease glaucoma. The term also means that the diminution, in the otherwise elevated intraocular pressure, obtained by the practice of the invention is maintained for a significant period of time as, for example, between consecutive doses of the composition of the invention. The renin inhibitors may be employed in the composition and methods of the invention as the sole IOP lowering ingredient or may be used in combination with other mechanistically distinct IOP lowering ingredients such as beta-adrenergic blocking agents, (e.g., timolol). For puroses of the present invention, the term beta-adrenergic blocker means a compound which by binding to beta adrenergic plasma membrane receptors reduces or eliminates sympathetic activity or blocks the effects of exogenously administered catecholamines or adrenergic drugs. See, for example, Weiner, N. , Drugs That Inhibit Adrenergic Nerves and Block Adrenergic Receptors, in The Pharmaceutical Basis of Therapeutics (ed. A.G. Goodman, L.S. Goodman, A. Gil an), Macmillan Publishing, New York, 1980, 6th ed., pp. 188-197. Examples of preferred beta adrenergic blockers are atenolol (4-[2-hydroxy-3-[( 1- methylethyl)amino]-propoxy] enzeneacetamide) , metoprolol ( 1-[4-(2-methoxyethyl)phenoxy] -3-[(1-methylethyl)amino]- 2-propanol), nadolol (5-[3-[(1_,1-dimethylethyl)amino]-2- hydroxypropoxy] -1,2,3,4-tetrahydro-2,3-naphthalenediol) , pindolol (l-(lH-indol-4-yloxy)-3-[(1-methylethyl)amino]- 2-propanol), propranolol (1-[(1-methylethyl)amino]-3-(1- naphthalenyloxy)-2-propanol) , timolol (1-[(1,1- dimethylethyl)amino]-3-[(4-morpholinyl-l,2,5-thiadiazol- 3-yl)oxy]-2-propanol) , labetalol (2-hydroxy-5-(1-hydroxy- 2-[(l-methyl-3-phenylpropyl)amino]ethyl]-benzamide) , betaxolol (1-[4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-3- [ (methylethyl)amino]-2-propanol) , carteolol (5-[3-[(1,1- dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)- guinolinone), and dilevalol ( [R-(R,R) ]-2-hydroxy-5-[1- hydroxy-2-[ (l-methyl-3-phenylpropyl)amino]ethyl]- bnezamide 4-methylbenzenesulfonate salt), and pharmaceutically acceptable salts and isomers thereof. The usefulness of beta adrenergic blockers for lowering intraocular pressure is known in the art. Thus, the beta adrenergic blocker timolol, is currently approved by the U.S. Food and Drug Administration for topical use as a treatment for glaucoma. It is marketed in two dose strengths, i.e., 0.25% and 0.5%. As previously stated, this agent must be used with caution in a defined patient population because of recognized untoward side effects (see Physicians Desk Reference for Ophthalmoloqy, 11th edition, 1983, p. 126, Medical Economics Co. Inc. , Oradell, N.J * 07649). As one aspect of the present invention, it is contemplated that a reduction in intraocular pressure equivalent to that obtained by use of a beta-blocker, e.g., the approved clinical dose of the beta-blocker timolol, may be obtained by use of a lower dose of beta- blocker when such lower dose is combined with an effective amount of a compound of formula I. It is anticipated that the use of the diminished dosage of beta-blocker, e.g., timolol, will result in a reduction of severity and frequency of timolol-like related side effects. For purposes of this combination treatment modality, the beta-blocker and compound of formula I are preferably administered simultaneously as one composition in one pharmaceutical dosage form. The beta adrenergic blocker may comprise from about 5 uq to about 125μq of the composition of the invention. The preferred ranqes of the components in the composition of the invention in unit dosaqe form are as follows: Beta adrenergic blocker: from 5 μg to 125 μg Renin inhibitor: from 1 ng to 0.1 mg. The individual dosage requirements, i.e., the amount of each dose and the frequency of administration, may vary dependinq on the severity of the disease and the response of the patient. Those skilled in the art will appreciate that the "intraocular pressure reducing concentration" for such combination therapy will consist of a range of concentrations (doses), and that there will be a lower limit to said concentration below which, the present invention will not operate. For purposes, of this invention, this lower limit or minimum dosage may be considered to be about 5% of the effective dose (threshold dose) of the particular component. The intraocular pressure reducing concentration that is actually utilized, whether for a compound defined in formula I or for a particular beta adrenergic blocker, will depend on, inter alia, the potency of each particular material, the combination being administered and the age, size and condition of the patient being treated as well as on the severity of the disease state. The elevation in IOP associated with the clinical ophthalmic and systemic use of anti-inflammatory steroids also can be reduced by the administration of a renin inhibitor. In particular, an increase in IOP is most often associated with the administration of steroidal anti-inflammatory agents. Anti-inflammatory steroids include hydrocortisone, cortisone, prednisolone, prednisone, dexa ethasone, methylprednisolone, triamcinolone, betamethasone, alclometasone, flunisolide, beclomethasone, clorocortolone, diflorasone, halcinonide, fluocinonide, flucinolone, desoximetasone, medrysone. paramethasone, 9,21-dichloro-17-[(2-furanylcarbonyl)oxy]- ll-hydroxy-16α-methyl-preqna-l,4-diene-3,20-dione and fluorometholone, and their pharmaceutically acceptable salts and esters. Preferred steroids are hydrocortisone, prednisolone, dexamethasone, betamethasone, beclomethasone, medrysone and fluoromethalone and their pharmaceutically acceptable salts and esters. This rise in IOP may occur with all modes of administration of the drugs, including systemic (usually oral), local injection (e.g., depot injection), and especially with ophthalmic topical or intravitreal administration. The renin inhibitor may be administered following steroid treatment to lower elevated .IOP, or may . be co-administered with the steroid to suppress the IOP-raising effect of the steroid while not interfering with the anti-inflammatory activity of the steroid. It is further contemplated that any possible combination of dosaqe forms may be used to administer the combination, e.g., oral steroid/topical renin inhibitor , topical steroid/oral renin inhibitor, oral steroid/oral renin inhibitor, topical steroid/topical renin inhibitor, and locally injected steroid/topical renin inhibitor, with a preferred combination comprising a steroid and a topical renin inhibitor. For ophthalmic use, a combination of a topical steroid and a topical renin inhibitor is preferred. More preferred is a topical ophthalmic pharmaceutical dosage form comprising both a steroid and a renin inhibitor. Such compositions or combinations can be employed in a method for reducing and controlling the elevated IOP associated with ophthalmic and systemic use of steroidal anti-inflammatory agents, which method comprises administering to a mammal effective amounts of a steroid and- a renin inhibitor, either separately or in the same pharmaceutical composition. Since the present invention relates to treatment with a combination of a renin inhibitor and a steroidal anti-inflammatory agent wherein the renin inhibitor and steroid may be administered separately, the invention also relates to combining separate pharmaceu¬ tical compositions in kit form, that is, combining two separate units, a renin inhibitor pharmaceutical composition and a steroid pharmaceutical composition, in a single package. Preferred components of the kit comprise a topical ophthamological renin inhibitor pharmaceutical composition and a pharmaceutically acceptable steroid composition. More preferred components of the kit are.a-topical ophthamological renin inhibitor pharmaceutical composition and a topical ophthamological steroid pharmaceutical composition. A particular advantage of the more preferred embodiment of the kit resides in the ability to provide a combination of a renin inhibitor composition which can be administered once or twice a day and a steroid composition which may be administered as frequently as once each hour. While the mechanism by which corticosteroids provide anti-inflammatory activity is unknown, their ability to provide ' relief from inflammatory symptoms is widely recognized. See, for example, Haynes, R.C. , Jr., and Murad, P. ' , "Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs, Inhibitors of Adrenocortical Steroid Biosynthesis" in The Pharmacological Basis of Theraputics (ed. , A.G. Gilman, L.S. Goodman, A. Gilman), Macmillan Publishing, New York, 1980, 6th ed., pp. 1470-1492, n.b. pg. 1490-1491. In this combination treatment modality, topical formulations of the invention may combine the following amounts of each inventive composition and steroidal constituent, or each constituent may be administered separately: Renin inhibitor from about 0.00001 to about 1.0 (w/v%) and especially about 0.00001 to about 0.1% of medicament. As a unit dosage form, an amount of renin inhibitor from between about 5 ng to about 0.5 mg, preferably about 5 ng to about 50 mg, and especially 5 ng to 25 ng of the active component is applied to the human eye. Individual dosage requirements, i.e., the amount of each dose and the frequency of administration, will depend on the potency of the particular renin inhibitor, the severity of the increase in IOP and the response of the patient. Steroid from about 0.05 to about 1.5 (w/v%) of medicament. As a unit dosage form, an amount of steroid from between 20 μg to 600 μg of the active composition is applied to the human eye. Individual dosage requirements, i.e., the amount of each dose and the frequency of ' administration will depend on the potency of the particular steroid, the severity of the disease and the response of the patient. Approximate ranαes for such steroids are well known to those skilled in the art. The particular steroid selected will determine which renin inhibitor and concentration thereof to select for use in a combination preparation. In one embodiment of the invention, both active ingredients, i.e., renin inhibitor and steroid, will be administered simultaneously and be contained in one pharmaceutical dosage form, each component being present in the dosage form in its own respective preferred concentration. When the steroid is administered systemically or topically other than in an ophthalmological composition, the concentration of the steroid in the composition and the unit dosage weight may vary considerably, depending as above on such factors as the potency of the steroid, its onset and duration of action as well as the severity of the disease, and the response of the patient. Appropriate dosage ranges for systemic and topical administration of each steroid are well known in the art. Those skilled in the art will know that for solutions and suspensions, a particular dosage of active ingredient may be calculated if one assumes that one drop of solution is being administered and if one knows the concentration (w/v) of the particular solution that is beinq administered. Thus, one drop (1/20 ml) of a 0.25% solution (contains 2.5 mq of active per ml) is known to contain .125 mq or 125 μg of active. The IOP-lowering effects of the compositions employed in the invention may be measured by the procedure described by Watkins et al. , J. Ocular Pharmacol. 1_ ( 2 ) :161-168, 1985. To prepare suitable dosage forms, the active compositions may be conveniently admixed with a non-toxic pharmaceutically acceptable carrier suitable for topical ophthalmolgic administration. Typical of such pharmaceu¬ tically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, petroleum based jelly, and .includinq also from 0.5 to 5% by weiqht of hydroxy- ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, and other water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose, alkali metal carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acids salts; ethylacrylates; polyacrylamides; natural products such as qelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch; as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum; and mixtures of these polymers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600; carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000; antibacterial components such as quaternary ammonium compounds; phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use; thi erosal; methyl and propyl paraben; benzyl alcohol; phenyi .ethanol; buffering ingredients such. as. alkali metal chloride, borate, acetate, gluconate buffers; antioxidants such as sodium metabisulfite, butylated hydroxyanisol (BHA) , butylated hydroxytoluene (BHT) and the like; and other conventional ingredients such as sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monopalmitylate, dioctyl alkali metal sulfosuσσinate, monothioglycerol, ethylenediamine tetracetic acid and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic alkali chloride vehicles, tris and the like. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. Inserts that are known in the art that are suitable for this use include those described in United States Patent Nos. 3,993,071; 3,986,510; 3,868,445; and 3,867,510. Solid water insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be utilized. The compositions of the invention may include additional therapeutic agents in addition to the renin inhibitor. For example antibiotics, anesthetics as well as other IOP-lowering agents may be present. The following examples are intended to illustrate, but not to limit, the present invention. In such examples. Compound A refers to BOC-Phe-His-Sta-Leu- (4-amido-l-benzyl-piperidine) . It is contemplated, however, that therapeutically effective amounts of other renin inhibitors as discussed above may be substituted in its place. Example 1 Topical Solution: Ingredients mg/ml Compound A 1.0 Dibasic Sodium Phosphate 10.4 Monobasic Sodium Phosphate 2.4 Chlorobutanol 5.0 Hydroxypropyl methylcellulose 5.0 Sterile Water ~ q.s. ad 1.0 ml l.ON NaOH" q.s. ad pH 7.4 Mix the ingredients under sterile conditions and using standard techniques to obtain the ophthamoloqical solution. Example 2 Topical Solution: Ingredients mg/ml Compound A 1.0 Timolol 5.0 Dibasic Sodium Phosphate 10.4 Monobasic Sodium Phosphate 2.4 Chlorobutanol 5.0 Hydroxypropyl methylcellulose 5.0 Sterile Water q.s. ad 1.0 ml l.ON NaOH q.s. ad pH 7.4 Mix the ingredients under sterile conditions and using standard techniques to obtain the ophthamological solution. Example 3 Topical Solution: Ingredients mg/ml Compound A 1. , 0 Dexamethasone Sodium Phosphate 1 . , 0 Dibasic Sodium Phosphate 10. 4 Monobasic Sodium Phosphate 2. , 4 Chlorobutanol 5 . , 0 Hydroxypropyl methylcellulose 5. . 0 Sterile Water q . , s . ad 1 i nl l.ON NaOH g . ι S . ad pH - 7. 4 Mix the inqredients under sterile conditions and using standard techniques to obtain the ophthamological solution. Again, other renin inhibitors and steroids can be employed in place of those listed in the formulation above, with the particular amounts varying depending on the druqs employed. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims: WHAT IS CLAIMED IS: 1. The use of a renin inhibitor for the manufacture of a medicament for reducing and/or controlling excessive intraocular pressure. 2. The use of a renin inhibitor as claimed in claim 1 characterized by the renin inhibitor being a topical opthamologically acceptable renin inhibitor. 3. The use of a renin inhibitor as claimed in claim 1 or claim 2 characterized by the renin inhibitor being utilized in combination with an ophthamologically acceptable carrier for topical use. 4. The use of a renin inhibitor as claimed in any one of claims 1-3 in combination with a beta-adrenergic blocking agent. 5. The use of a renin inhibitor as claimed in claim 4 characterized in that the beta-adrenergic blocking agent comprises timolol. 6. The use of a renin inhibitor as claimed in any one of claims 1-5 in combination with an anti- inflammatory steroid. 7. A kit comprising in separate containers in a single package a renin inhibitor in a topical ophtalmological carrier and a steroid in a pharmaceutically acceptable carrier. 8. The kit of claim 7 characterized by the steroid carrier being a topical, ophthamologically acceptable carrier. 9. A pharmaceutical composition suitable for treating the rise in intraocular pressure associated with the use of steroidal anti-inflammatory agents comprising a renin inhibitor and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9 further comprising a beta-adrenergic blocking agent. 11. The pharmaceutical composition of either claim 9 or claim 10 wherein the renin inhibitor comprises BOC- Phe-His-Sta-Leu-(4-amido-l-benzyl-piperidine) . 12. The pharmaceutical composition as claimed in any of claims 9-11 above characterized in that the beta- adrenergic blocking agent comprises timolol.

Inventors: WATKINS ROBERT WAYNE, WATKINS, ROBERT, WAYNE
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1986
Main classification: A61K9
IPC codes: A61K38, A61K45, C07K5