The present invention relates to novel pharmaceutical prepa¬ rations for oral administration, in particular to pharmaceutical preparations containing A) an extract of the moliusc Perna canali- culus, and B) a phar acεutically active substance which may cause irritation to the mucosae of the gastro-intestinal tract, and/or favor the formation of gastro-intestinal ulcers as side effects, and to the use of these preparations for the corresponding indi- cations envisaged for component B, as well as a ethod of counter- acting the irritant or ulcerative effect on the mucosae of the gastro- intestinal tract produced by a pharmacologically active compound as defined under B) by taking together with such compound si ultaneously or in succession a moliusc extract as defined under A.

The invention also provides a method of preventing, alleviating or treating gastro-intestinal irritation conditions, lesions, and/or ulcer formation by administering a moliusc extract as defined under A.

Drugs administered to persons for therapeutic reasons may have amongst their side effects the creation of gastric ulcers and stomach bleeding, which in some cases may be serious and could occasionally even threaten the life of the individual. The object of the present invention is to reduce or prevent the occurrence of such side effects in the stomach or intestine of the person taking such drugs. It has been found that such gastro-protective or anti-ulcer effects can be obtained by the additional intake of an extract from the green - lipped aussei, Perna Canaliculus, a moliusc which is indigenous to New Zealand, but which can be raised in Special faπs on the shores of other places.

A moliusc extract as defined under A) is any product obtainable from the flesh of the animal or its organs and suitable for being used for the preparation of pharmaceutical preparations, and in particular

a) the powder obtained by drying and grinding the whole of the flesh of the moliusc, b) the lipid extract mixture obtained by solvent extraction of the flesh of the molluscs or of the dry powder as mentioned under a), c) the powder obtained by drying and grinding the gonads of the moliusc, or d) the lipid extract mixture obtained by solvent extraction of the gonadsor of the dry powder as mentioned under c) .

The manufacture of these various preparations and extracts can be performed as follows:

with respect to a):

1) the outside of the shellfish is washed with high pressure hosing, and

2) the flesh is removed from the shell, for example, by hand, ensuring that no heat is applied, as the temperature should not exceed 10°C.

3) The product is tested for bacteria and heavy metal content, as only shellfish can be used which have no such contamination.

4) The flesh is placed in a grinding machine and pulverized into small pieces, then placed onto trays, preferably having an uniform thickness of about 3/4 inch,

5) and freeze-dried.

6) The freeze-dried aterial is then crushed into a fine powder and sealed, preferably into vacuum-packed Containers.

With respect to c) : The same procedure is followed as under a) , except that the gonads only are removed and used.

Thε lipids extract mixtures mentioned under b) and d) above can be obtained from the whole of the flesh or the gonads of the mussei by extraction with a suitable organic solvent capable of dis- solving lipids, such as a halogenated aliphatic hydrocarbon, for instance, ethylene or ethylene chloride, Chloroform or carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene, or the xylenes, or esters, such as ethyl acetate. The extraction can be performed in a manner known per se. The lipid extract mixtures ob¬ tained in this manner can be used directly for grinding, if the organic solvent extract has been suitably dried before being evapo- rated. Alternatively the dry extracts as described under a) and c) can be used for extraction with the said organic solvent.

A moliusc extract as indicated under c) is available on the market as a commercial product under the brand na e "Seatone" and is sold in pharmacies and health food stores e.g. in a number of . . countries, such as Canada, Australia, New Zealand, United Kingdom, Switzerland, Holland and Den ark, and is supplied by McEarlane Laboratories Ltd., 23/27 Heather Street, Partiell, Auckland N.Z. The substance is sold as a food Supplement in the above countries.

The composition of the mussei extract "Seatone" named above is as follows: moisture content: 0.65 % - 3.21 % (average = 2.23 %) lipid content: 0.67 % -10.54 % (average = 9.09 %) protein content: 52.13 % -55.60 % (average =53.57 %) carbohydrate content: 18.60 % -24.29 % (average =22.25 %) ; and ash content: 11.7 % -14.90 % (average =12.83 %.

Minerals (average percentages) sodium = 3.04 % potassiu = 0.94 % magnesium = 0.41 % calcium = 0.49 %

- 4 -

_* •_•

% zinc - 0.01 % copper = 0.00062 %

^• cadmium = 0.000027 % lead = 0.00016 % manganese = 0.00116 % . iron = 0.04 % ercury = 0.0000196 % nickel = 0.0006 % selenium = 0.000145 %.

In terms of amino acids the composition of the product is as follows:

Amino acids %

Cysteic acid 3,1

Aspartic acid 4,9

Threonine 2,

Serine 2,0

Glutamic acid 6,4

Proline 2,2

Glycine 4,2

Alanine 2,4

Valine 1,9

1/2 Cystine 0,6

Methionine 1,1

Iso-Leucine 1,8

Tyrosine 1,5

Phenylalanine 1,8

NH ₄ 0,6

L sine 3,2

Histidine 0,8

Arginine 3,5

"Seatone" and other similar extracts, such as the extracts a), b), c) and d) named above, obtained from the moliusc Perna

O

canaliculus have extremely low toxicity, and there has been no indication of any hazardous side effects and no contra-indication, apart from cases of persons being allergic to shellfish.

The component B) above can be any pharamacologiacally active substance which, when taken per os, may cause irritation to the mucosae of the stomach or intestine, and could favor the formation of ulcers. It is especially a substance having anti-phlogistic, anti- pyretic and/or analgesic action, e.g. one of the known substances having these properties. These substances can also be present in the pharmaceutical preparations according to the invention in the ^" ~. form of phar acεutically acceptable, non-toxic salts such as acid addition salts °r salts with bases.

Particularly suitable compounds having antiphlogistic, anti- pyretic and analgesic action are those of the salicylic acid type and derivatives thereof, especially salicylamide, of the pyrazolinone or pyrazolidinedione type, in particular phenazones, such as propyphen- azone or a inophenazonε, as well as phenylbutazone or oxyphen- butazone, and in addition compounds of the acyla inophenol type and their ethers, of the- aryl-lower alkanoic acid and aryl-lower alkenoic acid type, and also of the anthranilic acid type and similar compounds possessing antiphlogistic, antipyretic and analgesic properties, or pharmaceutically acceptable,non-toxic salts with bases or acid addi¬ tion salts of such compounds.

Active compounds of the salicylic acid type as defined herein are in particular compounds of the foπaula

(II)

wfaerein R. is hydrogen or acyl, such as lower alkanoyl, e.g. acetyl, and B.» is hydrogen or phenyl which is unsubstituted or substituted e.g. by halogen, such as fluorine, for example 2,4-difluorophenyl, or phaπnaceutically acceptable non-toxic salts thereof, as well as carboxylic acid derivatives of such compounds, such as esters and amides. Examples of compounds of this type are carboxylic acids, such as salicylic acid and O-acetylsalicylic acid, and 4-(2,4-difluoro- phenyl)-salicylic acid (diflunisal) or phaπnaceutically acceptable non-toxic salts thereof, furthermore esters, such as 4-acetylamino- phenyl O-acetylsalicylate (benorylate), and 3-phenylpropylsalicylate, -and amides, in particular salicylamide.

Compounds of the pyrazolinone type having antiphlogistic, anti- pyretic and analgesic action are in particular those of the formula

wherein R_ is a substituted or unsubstitutedcarbocyclic or heterocyc- lic radical of aromatic character, especially phenyl, 31, and R_ are lower alkyl, in particular methyl, and R, is hydrogen, lower alkyl which is unsubstituted or substituted e.g. by a substituted amino group, for example isopropyl, or substituted amino, such as lower alkyl- a ino, di-lower alkylamino, acylamino, N-acyl-N-lower alkylamino, N- (sulfomethyl)amino or N-(sulfomethyl)-N-lower alkylamino. Repräsentati¬ ves of this type of compound having antiphlogistic, antipyrεtic and analgesic action are 2,3-dimethyl-4-isopropyl-l-phenyl-3-pyrazolin- 5-one (propyphenazone), 2,3-dimeth l-4-(dimεthylamino)-l-ρhenyl-3-ρyra- zolin-5-one (aminophenazonε), 2,3-dimethyl-l-phεnyl-3-pyrazolin-5-onε (antipyrin), 2,3-dimethyl-4-(N-methyl-N-nicotinoyl-amino)-l-phεnyl-3- pyrazolin-5-one (methylnifenazine) , sodivi salts of (N-antipyrinyl- a ino)-πethansulfonic acid ( elansulfone) and of (N-antipyrinyl-N-

- 7 -

methyl-a__nino)-fflethanesulfonic acid [dipyrone (BAN, DSAN)], or 2,3-di- πιethyl-4-C-[4-N-(6-methoxy-3-ρyridaziny1)-sulfamoy1]-ani lino]-sulfo- methyl-l-phenyl-3-pyrazolin-5-one (sufenazone) .

Compounds of the pyrazolidinedione-type having antiphlogistic propertiεs are particularly those of the formula

wherein each of R' and R" is carbocyclic radical of aromatic character, such as optionally substituted phenyl, containing as substituent, for example, hydroxy, and Rl is optionally substituted lower alkyl, containing as substituent, for examplε, oxo. Rεprεsentative members of this group of compounds are, for example, l,2-diphenyl-4-n-butyl- pyrazolidin-3,5-dionε (phenylbutazone)and 1- (4-hydroxyphεnyl)-2- pheny1-4-n-buty1-pyrazolidine-3,5-dione (oxyphenbutazone) .

Compounds of the acyl minophenol type as defined herein are in particular compounds of the formula

wherein is lower alkyl which is unsubstituted or substituted e . g . by hydroxy 1, for example ethyl or 1-hydroxyεthyl , and g is hydro ^¬ gen or lower alkyl . Compounds of this type are, inter alia, N-acetyl- 4-ethoxy-aniline (phenacetin) , 4-ethoxy-N-(2-hydroxyprcpionyl)-aniline (lactophenin) oder 4-acεtyl a ino-phenol (paracetamol) .

C PI fi~ W1PO -z

Compounds of the anthranilic acid type as defined herein are e.g. compounds of the formula

wherein is the group of the formula -CH-CH-, -S- or -CH*N-, and R is phenyl which is unsubstituted or substituted by lower alkyl, e.g. methyl, halogen, e.g. chlorine, and/or trifluoromethyl, or is quinolin- yl which is unsubstituted or substituted by halogen, e.g. chlorine, and/or trifluoromethyl, for example corresponding 4-quinolinyl, or pharmaceutically acceptable non-toxic salts thereof or esters, for example lower alkyl esters of such compounds which are unsubstituted or substituted by hydrosyl, lower alkoxy, e.g. oethoxy or ethoxy, or lower alkanoyloxy, e.g. acetyloxy. Representatives of this class of active compounds as defined herein are e.g. N-(3-trifluoromethyl- phenyl)-anthranilic acid (flufenamic acid), N-(2,3-dimethyl-phenyl)- aothranilic acid (mefenamic acid), N-(3-chloro-2-methyl-phenyl)-anthra¬ nilic acid (tolfenamic acid), N-(2,6-dichloro-3-oethyl-ρhenyl)-anthra- nilic acid (meclofenamic acid), 2-(3-trifluoromethyl-anilino)-nico- tinic acid (niflu ic acid), 2-(2,3-dimethyl-anilino)-nicotinic acid, 2-(3-chloro-2-methyl-anilino)-nicotinic acid (clonixin odεr clσnixi- dinε), 2-(2-methyl-3-trifluoromethyl-anilino)-nicotinic acid (flumixin) N-(2,6-dichloro-3-methyl-ρhenyl)-anthranilic acid ethoxymethyl estεr (etoclofen), 4-(2-chloro-3-methyl-anilino)-3-thiophenecarboxylic acid acetyloxymethyl ester (aclantate), N-(8-trifluoromethyl-4-quinolinyl)- anthranilic acid 2,3-dihydroxy-propyl ester (floctafεninε) , N-(7- chloro-4-quinolinyl)-anthranilic acid 2,3-dihydroxy-propyl ester (gla- phenine), 2-(3-chloro-2-methyl-anilino)-nicotinic acid 2,3-dihydroxy- propyl ester (clonixeril) or 4-(8-trifluoromethyl-4-quinolinylamino)- 3-thioρhenecarboxylic acid 2,3-dihydroxy-propyl ester, and pharma¬ ceutically acceptable non-toxic salts thereof.

BU Q O.:-

In active arylalkane- or arylalkenecarboxylic acid compounds as defined herein, aryl is in particular. a preferably substituted carbocyclic hydrocarbon radical of aromatic character; but it can also be a substituted or unsubstituted heterocyclic radical of aromatic character. Preferably, aryl-lower alkanecarboxylic acid compounds are substituted phenylalkanecarboxylic acid compounds of the formula

^R 13 ^R 1

wherein R is in particular lower alkylidene and most preferably methylene or ethylidene, and also propylidene, or lower alkylene or lower alkenylene which is unsubstituted or substituted e.g. by oxo, for example l-oxo-l,3-propylene, R „ is hydrogen, lower. alkyl, e.g. isobutyl, cycloalkyl or cycloalkεnyl, for example cyclohexyl or 1- cyclohexenyl, unsubstituted or substituted phenyl, lower alkoxy or lower alkenyloxy, e.g. n-butyloxy or allyloxy, lower alkyleneamino or lower alkenyleneamino which is unsubstituted or substituted e.g. in the aliphatic moiety by oxo or lower alkyleneamino or lower alkenylene¬ amino which contains a fused benzo moiety, e.g. 3-pyrrolin-l-yl or l-oxo-2-isoindolinyl, or acyl, such as aroyl, wherein aryl is a sub¬ stituted or unsubstituted carbocyclic hydrocarbon radical of aromatic character or a heterocyclic radical of aromatic character, e.g. the- noyl, R _ is hydrogen, halogen, ε.g. chlorinε, aryloxy, wherein aryl is prefεrably a substituted or unsubstituted carbocyclic hydrocarbon radical of aromatic character, e.g. phenyloxy, or acyl, in particular aroyl, wherεin aryl is preferably a carbocyclic hydrocarbon radical of aromatic character which is unsubstituted or substituted e.g. by halogen, such as chlorinε, for εxamplε bεnzoyl or 4-chlorcbenzoyl, and R , is hydrogen, lowεr alkyl, for example methyl, or is phenyloxy which is unsubstitutεd or substituted ε.g. by halogen, such as chlorine, -for example 2,4-dichlorophenyloxy, amino or anilino which is unsub-

•j .-

stituted or substituted e.g. by halogen, such as chlorine, for example

2,6-dichloroanilino, with the proviso that at least one of the groups

R,„, R,_ and R„ , is hydrogen and at least one of the is different 12 13 14 from hydrogen, or pharmaceutically acceptable non-toxic salts of such compounds, and also carboxylic acid derivatives, for example esters, such as lower alkyl esters which are unsubstituted or substituted by hydroxy1 or etherified hydroxy1, or hydroxamic acids thereof. Repre- sentatives of these compounds possessing antiphlogistic properties are, inter alia, 2-(4-isobutyl-ρhenyl)-propionic acid (ibuprofen) , 2-(4-n-butyloxy-phenyl)-acetohydroxamic acid (butexamac), 2-(4-allyl- oxy-3-chloro-ρhenyl)-acetic acid (alclofenac), 2-(4-biρhenylyl)- butyric acid (buticiclate), 2-[3-(4-chlorobenzoyl)-2-methyl-ρhenyl]- acetic acid 2,3-isσpropylidεnedicx^-propyl ester , 2-[4-(2-thenoyl)- phenyl]-propionic acid (suprofen), 2-[3-benzoyl-pheπyl)-propionic (ketoprofen), 2-(3-phenyloxy-phenyl)-propionic acid (fenoprofen), 4-(3-chloro-4-cyclohexyl-ρhenyl)-4-oxo-butyric acid, 2-[4-(l-oxo-2- isoindolinyl)-phenyl]-propionic acid (indoprofen), 2-[4-(3-pyrrolin- l-yl)-phenyl]-propionic acid (pirprofen) , 2-(2-amino-3-benzoyl-phenyl)- acetic acid, 2-[2-amino-3-(4-chlorobenzoyD-phenyl]-acetic acid, 2-[2-(2,4-dichlorophenyloxy)-phεnyl]-acεtic acid (fεnclofεnac) or 2-[2-(2,6-dichloroanilino)-phenyl]-acεtic acid (diclofenac), or pharmaceutically acceptablε salts of such compunds.

A further group of aryl-lower alkanecarboxylic acid and aryl- lower alkenecarboxylic acid compounds comprises those of thε formula

wherein R is in particular lower alkylidene and ost particularly methylene and ethylidenε, or is lower alkylene or lower alkylidene

which is unsubstituted or substituted e.g. by oxo, and one of the groups R.g is hydrogen and the other together with R - forms a cyclo- aliphatic, aromatic or hεtεrocyclic ring which is unsubstituted or substituted e.g. by lower aikyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as chlorine, oxo, or by phenyl which is unsubstituted or substituted e.g. by halogen, such as chlorine, and which can contain a fused cycloaliphatic, aromatic or heterocyclic ring, and L» is hydrogen or halogen, e.g. chlorine, or pharmaceuti¬ cally acceptable non-toxic salts of such compounds. Examples of active compounds of this kind as defined herein are 2-(10-methyl-2-pheno- thiazinyD-acεtic acid (methiazinic acid), 2-(7-methoxy-10-mεthyl-2- phenothiazinyD-propionic acid (proctizinic acid) , 2-(6-methoxy-2- naphthyD-propionic acid (naproxεn), 2-[2-(4-chlorophenyl)-5-benzoxa- zolyl]-propionic acid (benzoxaprofen) , 2-(2-ρhenyl-5-benzthiazolyl)- acetic acid,2-(2-phenyl-5-benzthiazolyl)-propionic acid, 2-(7-fluoreny]>- propionic acid (cicloprofen), 2-(ll-cκo-2-dibenzoxepinyl)-acetic acid, 2-(2-chloro-4,5-isopropylidenedioxyphenyl)-acetic acid, 2-(3-phenyl- 7-benzofuranyD-propionic acid, 2-(5,6,7,8-tetrahydro-2-carbazoly1)- acetic acid, 2-(6-carbazolyl)-propionic acid, 2-(l-chloro-6-carbazol- yl)-propionic acid, 2-(9-oxo-2-xanthenyl)-proρionic acid, 4-(2-di- benzofuranyl)-4-oxo-butyric acid (furobufen) or 2-(5H-[l]benzo- pyrano[2,3-b]pyrid-7-yl)-propionic acid or pharmaceutically acceptablε non-toxic salts of such compounds.

A further group of aryl-lower alkanecarboxylic acid or aryl- lower alkenecarboxylic acid compounds, wherein aryl denotes a hetero¬ cyclic group of aromatic character, comprises compounds of thε formula

Ar - R . - C00H (VIII)

wherein Ar. is a monocyclic aza-, thia-, thiaza- or oxazacyclic radical of aromatic character which is unsubstituted or substituted e.g. by lower alkyl, such as methyl, phenyl which is unsubstituted or substi-

tuted e.g. by halogen, such as chlorine, or acyl, such as benzoyl whic is unsubstituted or substituted by lower alkyl, such as methyl, and R is lower alkylidene, e.g. methylene or ethylidene, and also lower alkylene or lower alkenylene, or pharmaceutically acceptable non- toxic salts thereof. Exa ples of such compounds are, inter alia, 2-[l-methyl-5-(4-methylbenzoyl)-2-pyrrolyl3-acetic. acid (tolmetin), 2-[l-(4-chlorophenyl)-2,5-dimethyl-3-pyrrolyl3-acetic acid (clopirac) 2-(5-benzoyl-2-thienyl)-propionic acid (thiaprofenic acid), 2-(4,5- diphenyl-2-oxazolyl)-propionic acid (oxaprozin), 2-[4-(4-chloro- phenyl)-5-thiazolyl]-acetic acid, 2-[2-(4-chlorophenyl)—4-thiazolylJ- acetic acid (fenclozinic acid), 3-[2-(4-chlorophenyl)-4-thiazolyl]- acrylic acid or 2-[3-(4-chlorophenyl)-2-phenyl-5-thiazolyl]-acetic acid (fentiazac).

A further group of aryl-lower-alkanε- or aryl-lowεr-alkene carboxylic acids arε those of the formula

wherein R _ is a methylenε group, which may optionally bε substitutεd, e.g. by an aralkylidenε group, e.g. 4-methylsulfinyl-benzylidenε, or a nitrogεn or sulfur atom which may optionally bε substitutεd by an aroyl-, aryl lowεr alkanoyl- or aryl lowεr alkεnoyl group, ε.g. 4- chlorobenzoyl or 3,4-methylenedioxy-bεnzoyl, onε of the groups R.. , and R,_ reprεsents the residuε of thε formula -(CH_) _n . - COOH and 15 z υ. L thε othεr hydrogen or lower alkyl, especially methyl, and in which preferably at least one of the groups R and R represεnts a substi¬ tuent, ε.g. cycloalkyl, e.g. cyclohexyl, lowεr alkoxy, ε.g. methoxy, halogen, ε.g. chlorinε, or acyl, such as ε.g.bεnzoyl containing halogεn, ε.g. chlorine, ε.g. benzoyl or 2-chloro-benzoyl, while the other may reprεsent hydrogεn or a substituεnt, for instance hydroxy or halogεn, e.g. chlorine, there being optionally present in the five-

mεmbered ring betweεn thε C-atoms 2 and 3 a doublε bond, or pharma- cεutically acceptable non-toxic salts of such compounds, and acid dεrivatives thereof, for instance the corresponding amides, e.g. the glucosämides or tεtrazole compounds. As examplεs of this group of compounds there are to be mentioned among others: 2-[l-(4-chloro-ben- zoyl)-5-methoxy-2-methyl-3-indόlyl] acetic acid (indomethacine) 5-cyclohexyl-l-indane carboxylic acid, 6-chloro-5-cyclohexyl-l-indanε carboxylic acid, l-(4-chloro-benzoyl)-3-(5-tεtrazolylmεthyl)-indole (intrazole), 2-(l-cumaramoyl-5-methoxy-2-methyl-3-indolyl) acetic acid (cinmetazine) , 2-[5-methoxy-2-methyl-l-(3,4-methylenedioxy-benzoy1)- 3-indolyl]-acεtic acid, 2-(5-chloro-3-methyl-2-benzothiεnyl)-acεtic - acid,.2-[5-fluoro-2-methyl-l-(4-methylsulfinyl-bεnzylidεn� �)-3-indenyl] acεtic acid (sulindac) and 2-[l-(4-chlor-bεnzoyl)-5-methoxy-2-methyl- 3-indolyl]-acεtic acid-glucosεamide (indosamidε) or pharmaceutically accεptable, non toxic salts of these compounds.

Suitable salts of the above mentioned compounds, and also of those referr.ed to hereinafter, with basic properties. are pharmaceu¬ tically acceptable non-toxic acid addition salts with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, aleic acid, hydroxymaleic acid, ethyl aleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenz- oic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, for example ethane- sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-l,2-disulfonic acid, bεnzenesulfonic acid, 4-methylbenzene- sulfonic acid or naphthalεne-2-sulfonic acid.

Salts of the above compounds with acid properties are in par- ticular metal or ammonium salts, such as alkali metal salts and alka- line earth metal salts, for example sodium, potassium, agnesium or calcium salts, and ammonium salts with ammonia or suitable organic a ines. Suitable amines for the salt formation are in particular aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and also heterocyclic bases; such as lower alkylamines, for example triethyl- amine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, and basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-di ^' ethylamino- ethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cyclo- alkylamines, e.g. dicyclohexylaminε, or benzylamines, e.g. N,N'-di- benzylethylenediamine, as well as bases of the pyridine type, e.g. pyridine, collidine or quinoline.

The compounds mentioned above and hereinafter which contain centres of asymmetry can be emplσyed in the form of race ates or of optically active antipodes, or in the case of diastereomerism, also in the form of racemate mixtures.

The dose of the component B having antiphlogistic, antipyretic and analgεsic action variεs greatly. Thus compounds of thε salicylic acid typε, i.e. those of the formula II, for example salicylamide or acεtylsalicylic acid, can be administ.ered to war -blooded animals having a body wεight of about 60 to 70 kg. ε.g. in singlε doses of äbout 25 to 250 mg (in daily dosεs of about 50 to about 1500 mg) , compounds of the pyrazolinone type, i.e. those of thε formula III, e.g. 2,3-dimethyl-4-isopropyl-l-phenyl-3-pyrazolin-5-one (propyphen- azonε) or 2,3-dimεth l-4-(dimethylamino)-l-phenyl-3-pyrazolin-5-one (aminophenazone) in singlε doses of about 25 mg to about 250 mg (in daily doses of about 50 to about 500 mg) , compounds of the acylamino- phenol type, i.ε. those of thε formula IV, in Single doses of about 200 to about 600 mg (in daily doses of about 400 mg to about

1500 mg), compounds of the anthranilic acid type, i.e. those όf the formula V, in single doses of about 25 mg to about 250 mg (in daily doses of about 50 mg to about 500 mg), and compounds of the arylalkane- or arylalkenecarboxylic acid type, i.e. those of the foππulae VI to VIII, in single doses of about 50 mg to about 500 mg (in daily doses of about 150 mg to about 1500 mg)..

The preferred single doses to be administered to a waπn-blooded animal having a body weight of about 60 to 70 kg,for instancε f _Q r the compounds dielofenac sodium and phenylbutazonε are 25 - 100 mg and 75 - 200 mg respectively,whereas the daily doses are 100 -200 mg and 200 - 600 mg respectively.

The ratio in weight between the componentA) in the formof an extract a) or c) as defined above and the component B) in the pharmaceutical preparations aecording to the invention can vary within wide limits, but a ränge bεtwεεn 1:1 and 50:1 is prefεrred, εspεcially bεtween 4:1 and 20:1. A ratio of approximately 10:1 is particularly recommended. Naturally, the higher the proportion of moliusc εxtract to component A is, thε grεatεr the gastro - protective εffect of the mi turε.

The lipid fractions b) and d) are up to about 8 - 10 percent by weight of the extract a) and c) . Therefore, if componεnt B is being ixed with the lipid fractions b) or d) , the ratio A to B should be co mεnsurate with those expressed above for the moliusc extract.

In the pharmaceutical preparations aecording to the present invention the two components A and B can both be present as a mixturε in one and thε same dosage unit form e.g. in a tablet or capsule, however, they can also be in the form of two dosage unit forms for each of the components A and B, to be taken at the same ti e.

-BÜ REÄCΓ

O PΪ -% _^ WiPO ,*V

«

The dosage of the unit forms of the new preparations depends on thε particular componεnt B used. Prεfεrably it is the same as that currently usεd for the particular, pharmaceutically activε compound, when taken alone, but it can be also an aliquot or a multiple of it, depεnding on the circumstancεs, ε.g. it can be about half or a third or a-fourth of the dosε nor ally usεd.

In addition to the components A and B, the preparations of the presεnt invention normally contain suitable carriers and adjuncts which assist the incorporation of thε activε components. into the preparations. The preparations can be for instance in the form of tablets, film coated tablets, sugar coated tablets or capsulεs, or as suspεnsions in Containers, such as bottles or plastics,thε contεnt of activε ingrεdiεnt being of about 10 % - 100 %. In the solid forms, e.g. those named above, the carriers can be the samε as thosε occuring in the known preparations containing active compounds corrεsponding to the component B, the ratio of active substance to carrier being the same,and the amount of active substance being the sum of the components A and B, but it can also- vary widely from this ratio within thε ränge given abovε. Prεfεrably thε contεnt of activε substance in the new preparations is about 20 % - about 100 %, in particular about 50 % - to about 90 %.

Suitable carriers are in particular fillers, such as sugar, ^' for example, lactose, Saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphates,alsobinders such as starch pastes, for example maize, com, rice or potato starch paste, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiu carboxymethyl- cellulose and/or polyvinylpyrrolidone, and/or, if desired, disinte- grators, such as the above starches, also carboxymethyl starch, cross- linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are chiεfly glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesiu stearate or calcium stearatε,, and/or polyethylεne glycol

-^ΪTR

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or fatty substances such as hydrogenatεd cotton oil.

Sugar-coated tablet cores are provided with suitable coatings that can be resistant to gastric juices, using, inter alia, concentrated sugar Solutions which may contain ^~ υ arabic, talc, polyvinylpyrrolidone, polyfcthylene glycol and/or titanium dioxide, shellac Solutions in suitable organic solvente or solvent mixtures or, for the preparation of coatings resistant to gastric juices, Solutions of suitable cellu¬ lose preparations, such as acetylcellulose phthalate or hydroxypropyl- oethylcellulose phthalate. By incorporating one or more active com¬ ponents into a suitable carrier which effects a slov release of the active component or components, 'it is possible to prolong the action of one or more components which in themselves have an action of short duration. Dyes or pigments can be added to the tablets or sugar-coated tablet cores, for example to identify or indicate different combina- tions of doses of the active components.

Further pharmaceutical preparations for oral administration are dry-filled capsules, and also soft sealed capsules made from gelatin and plasticiser, such as glycerin or sorbitol. The dry-filled capsules cancomtain the active ingredient in the form of granules, for example in admixture with fillers such as maize starch, binders and/or lubri- cants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active components are preferably dissolved or suspended in suitable liquids, for example in fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers, e.g. lecithins, can also be added.

The pharmacεutical preparations of thε invεntion may also includε bεsidεs thε said components A) and B) and the phar acεuticals carriers mentioned other pharmaceutically active compounds, such as vitamins, or compounds having a protεctive action on the mucosae of the gastro- intεstinal tract, such as oxides or hydroxides or basic salts of metals like alu inium, magnesium, bis uth, for instance colloidal

aluminium trihydroxide or magnesium trisilicatε. Vitamin B, is especially to be mentioned as possible supplementary pharmaceutical ^• contained in the new preparations.

In the case that the pharmaceutical preparations of the presεnt invεntion arε in the form of two separate dosage unit forms for the components A and B, the component A may be in a solid form, ε.g. a tablet or capsule, or in liquid form, e.g. as a soft capsule, including a Suspension of the moliusc extract, and B may be in any form, aecording to the nature of the antiphlogistic to be used,ε.g. also in solid form or as a suspεnsion or a solution, for instancε an aquεous solution ε.g. of a solublε metal salt, such as a sodium salt, or in the form of a syrup containing, about 1 % to about 12 % of the active component.

The pharmaceutical preparations of this invention are prepared in a manner known per se, for example by conventional mixing, granu- lating, sugar-coating, solution and lyophilising methods. Pharmaceu¬ tical preparations which are suitable for oral administration can be obtained by combining the active components with solid carriers, op¬ tionally granulating the mixture thereby obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable adjuncts, to tablets or sugar-coated tablet cores.

In particular, for preparing solid forms of the prεparations containing thε mixturε in one singlε dosagε unit form, the component A, in the form of a moliusc extract as mentioned under a) , b) , c) or d) above, is ixed in a manner known per sε with a solid component B, and thε rεsulting mixture is incorporatεd in a solid dosagε form, for εxa plε, a capsulε or tablεt, for oral admini¬ stration. In thε casε that aquεous forms are chosen for the new prεparations,either an aquεous solution or a suspεnsion of thε component B is mixεd with an aquεous Suspension of thε moliusc extract A and thε rεsulting Suspension is fillεd in suitable Contai¬ ners, for instance, bottles or flasks, or the components ^' .. _*~ *rr~'

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A and B are mixed in the solid State and a suitable suspending agent, such as tracaganth, is added, then the required amount of water is addεd and the Suspension filled in the desirεd containεrs, or thε- components A and B are mixεd in solid form togεther with a suspending agent and this solid mixture is filled in suitable _C ontai¬ ners, the rεquirεd amoun of water being added when the drug is taken by the patient and thε containεr being closεd and shakεn so as to obtain an uniform suspεnsion.

A second aspect of the present invention is a method for counteracting the irritant or ulcerating side effect of pharamaceuti- cally activε compounds on the gastro-intεstinal mucosaε or for prεven- ting or reducing the formation of gastro-intestinal ulcers consisting in administering concomitantly or in succession with the said pharma¬ ceutically active compound an amount of an extract of the moliusc Perna canaliculus. The moliusc extract is e.g. any of the extracts a) , b) , c) and d) named above in relation to the pharmaceutical preparations of the prεsεnt invention. The pharmaceutically active compound refεrrεd to in this method are above all antiphlogistics, antirheu- matic or analgesics, especially those reported above. One way to ob¬ tain the desired gastro-protectivε result aecording to this new method is the administration of any of the pharmaceutical preparations just describεd. Howevεr, thε mεthod also εnvisages the administration of the antiphlogistic and the moliusc extract at different ti es, in which case thε doses to bε chosεn for the moliusc εxtract are prefεrably thε same as presεnt in thε said pharmacεutical prεparations.

Thus an amount varying e.g. from 1 to 50 times thε wεight of thε pharmaceutically active compound, ε.g. an antirhεumatic, and prεferably from 4 to 20 times such weight, of the moliusc extract is employed.

A third aspect of the present invention is a method for preven- ting, alleviating or treating gastro-intestinal irritation conditions, lesions and or ulcer formation, consisting in administering to a

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patiεnt an effective amount of an extract of the moliusc Perήa.canali- culus.

It has been found that the protective and therapεutical εffεcts on the mucosae of the gastro-intestinal tract of extracts of the New-Zealand green-lipped mussei named above does not εnsuε only in thε prεsence of a pharmaceutically active compound having an irritant action on the mucosae of thε gastro-intestinal tract, but also when taken per se. Thε said εxtracts can thus bε used as a profilactic or therapeutical agent also in cases where gastro-intestinal irritation conditions or bleεding or ulcerationare of other origin than those caused by pharmacεutically active compounds.

Any of the moliusc extracts a) , b) , c) and d) describεd abovε in rεlation to the pharmaceutical preparations of the invention can be used aecording to this new method of prevention or treatment. Thεrε is prεferably usεd an εxtract aecording to c), that is an εxtract of the gonads, or a corrεsponding lipid fraction aecording to d) . Thε dosεs usεd may vary within a widε rangε, the product having a very low dεgree of toxicity.

Thε doses may also vary widεly aecording to thε nεcessitiεs and thε naturε of thε disεase to be treatεd. As a rule, the greatεr thε dose is, thε grεater the anti-irritant or anti-ulcεrogenic effect is.

For a moliusc extract of the type c) above,e.g. for a product having a similar composition as the food-supplemεnt "Sεatone", mentio¬ ned above, the doses are preferably 200-5000 mg per day for a patient of about 60-70 kg weight. A daily dose ränge between 280-1000 mg pεr day is rεcommended, the trεat ent being continued for many days until thε undesirεd Symptoms disappear. Thε trεatment can then be continued for some time at lower dosage, for instancε 200 - 250 mg pεr day. The doses to be usεd for thε lipid εxtracts b) and d) entionεd above are corrεspondingly rεduced to about 10 % of thε dosεs just mentioned.

Themoliusc extracts to be used in the method here describεd for treating gastro-intεstinal ulcεrs or prε-ulcεr-conditions can be in the form of suitable pharmaceutical preparations, similar or equal to those described above for the mixtures of mussels extracts and pharmaceutically active compounds. The dosage unit forms are preferably those corresponding to the daily doses to be administered reported abovε or aliquots or multiple therεof, e.g. one half to one third of those doses, or especially in the case of the lipids extracts, 2-5 times the quantity of the said doses.

The pharmaceutical preparations of the present invention are suitablε for the treatment of the same diseases as envisagεd for thε medicamεnts including compounds of the typε of component B) , for instance the known antiphlogistics, antipyretics or analgesics namεd above. As the addition of the moliusc extract [component A] does not impair the therapeutic effect of the said pharmaceutically active compounds and the medicamεnts containing thεm, the doses of the active substance of thε lattεr can also be the same in the pharmaceutical preparations of this invention in the form of component B, and such doses can serve as a basis for thε -manufacturε of the nεw prεparations.

The following Examplεs illustrate thε invention, but in no way limit thε scopε thereof. The temperatures are given in dεgrees centigrades (Cεlsius) .

Examplε 1; A hard gelatine capsule is filled with 300 mg of 0-acεtyl- salicylic acid mixed with 300 mg of moliusc extract of Perna canali- culus as available in commerce under the trade mark "Seatone" (McFarlane Laboratories Ltd., Auckland, NZ) [designated in the following Examples simply as "Seatone"], 5 mg of magnesium stearate and 50 mg of sodium carboxymethyl starch.

Example 2: A hard gelatine capsule is filled with 300 mg of 0-acetyl- salicylic acid mixed with 300 mg of the lipid fraction obtained by solvent extraction from thε product "Sεatone", 5 mg of magnesium stearatε and 50 mg of sodium carboxymethyl starch.

Example 3: A hard gelatinε capsulε is fillεd with 25 mg of diclofεnac sodium prεviously granulatεd with 2.5 mg Polyvinyl pyrrolidone K 30 in ethanol, mixεd with 250 mg of "Seatonε", 3 mg of magnεsium stearate and 100 mg of com starch.

Example 4: A hard gelatine capsule is filled with 50 mg of diclofenac sodium, previously granulated with 5 mg Polyvinylpyrrolidone, mixed with 250 mg of "Seatone", 4 mg of magnesium stearate and 70 mg of com starch.

Example 5: A hard gelatine capsule is filled with 100 mg of phenyl- butazonε, prεviously mixεd with 50 mg of lactose and 80 mg of com starch and granulatεd with 10 mg of Polyvinylpyrrolidonε K 30 dissolved in water, and 250 mg of "Seatone" together with 25 mg of talc, 1.5 mg of magnεsium stεaratε and 1.5 mg of colloidal silica.

Exampia 6: A hard gεlatine capsule is filled with 100 mg of oxyphenylbutazonε, mixεd with 100 mg of the lipid fraction obtainεd from the driεd powdεr of thε wholε flεsh of thε moliusc Perna canaliculus togεthεr with 25 mg of talc, 1.5 mg of magnesium stearate and 1.5 mg of colloidal silica.

Example 7: A hard gelatine capsule is filled with 25 mg of indometha- cine, previously mixed with 30 mg of lactose, 20 mg of corn starch and 20 mg. of sodium carboxymethylcellulose and granulated with 6 mg of starch past and 2 mg Aerosil 200 (trade mark) (silicagel), mixed with 250 mg of Seatone, 22 mg of cellulsoe and 5 mg of magnesium stεaratε.

Example 8: A hard gelatine capsule is filled with 50 mg of tolmetin mixed with 250 mg of Seatone and 100 mg of corn starch.

Example 9: Hard gelatinε capsulεs of "Seatonε" containing a corε in form of a tablet including diclofenac sodium.

A hard gelatinε capsule containing 250 mg of Seatone is prepared, the core of which capsule is constituted by a tablεt containg 25 mg of diclofenac sodium and has the following composition

Diclofεnac sodium 25,0 mg

Polyvinylpyrrolidon 2,0 mg

Cellulose powder 7,1 mg

Lactose 20,0 mg

Highly dispersed silicim dioxide 2,0 mg

Sodium-carboxymethyl-starch 16,0 mg

Talc. 2,5 mg

Magnεsium stεarate 1,5 mg

Total 68,0 mg

Example 10: Combination "blister" package containing "Seatone" and - acetyl - salicylic acid.

In a combination blister package each foil contains two rows of different dosage unit forms, one of tablets containing each 300 mg of acetyl salicylic acid (and any of the normal carriers used for tablets) and the other of capsules containing 600 mg of "Seatone".

Example 11; Capsule containing 300 mg of a gonad extract of Perna canaliculus having a composition corresponding to thε product "Sεatone" defined above and prεpared as described abovε.

Such capsulε can be taken daily for the treatmεnt of gastro-intεstinal irritation or ulcers aecording to the indications made above.

Example 12: Capsule containing a daily dose of 30 mg of a lipids mix¬ ture obtained by extracting the product Seatone with an organic lipid solvent, such as carbon tetrachloridε or Chloroform, for the treatment for gastro-intestinal ailements as indicated in Example 11.

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