Antihyperglycaemic Agent

Abstract

N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide of the formula and its non-toxic salts have a good antihyperglycaemic effect, which even surpasses that of some commercial biguanides. 2 Claims, No Drawings

Description

The present invention relates to the pharmaceutical use of a known biguanide, N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide, and its non-toxic salts, as antihyperglycaemic agents.

It is known that a number of substituted biquanides have a blood sugar depressing effect. For examples, phenylethyl-biguanides, butyl-biguanide and N,N-dimethyl-biguanide are commercially available as anti-diabetics. On the other hand, N.sup.1 -aryl-N.sup.5 -alkyl-biguanides are thought to have only a poor antidiabetic effect [B. Elpern, Ann.N.Y. Acad. Sci. 148, 577 (1968)]. For N.sup.1 -p-chlorophenyl-N.sup.5 -isopropyl-biquanide ("Proguanil hydrochloride"), for example, there has been described a slight blood sugar depressing effect which occurs only with toxic doses [K.K. Chen and R. C. Anderson, J. Pharmacol. Exp. Therap. 91,157, (1947)]. Surprisingly, it has now been found that N.sup.1 -phenyl-N.sup.5 -isopropyl-biquanide of the formula: and its non-toxic salts have a good antihyperglycaemic effect which even surpasses that of the aforesaid commercial biguanides.

Accordingly, the present invention provides an antihyperglycaemic pharmaceutical composition containing N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide as an active ingredient or a non-toxic salt thereof, in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier as hereinafter defined.

In the present specification the expression "pharmaceutically acceptable diluent or carrier" means a non-toxic substance that when mixed with the active ingredient or ingredients renders it suitable for administration. The expression excludes water, methanol, ethanol, butanol, .beta.-ethoxyethanol, and other low-molecular weight organic solvents commonly used in chemical synthesis, except in the presence of other pharmaceutically necessary ingredients such as salts in correct quantities to render the composition isotonic, buffers, surfactants, coloring and flavoring agents, and preservatives. Examples of suitable liquid diluents and carriers are vegetable oils, polyols, buffered aqueous solutions, isotonic saline aqueous solutions, syrups and lotion bases. Examples of suitable solid diluents and carriers are starches, cellulose and its derivatives, sugars, stearates and stearic acid, talc, and ointment bases.

Preferred pharmaceutical compositions of the invention are those adapted for oral administration. The diluents and carriers used are preferably therefore those that adapt the active ingredient or ingredients for oral administration. Examples of such diluents and carriers are solid vehicles, excipients and lubricants such as glucose, lactose and sucrose, corn and potato starch, sodium carboxymethyl-cellulose, ethyl cellulose and cellulose acetate, powdered gum tragacanth, gelatin, alginic acid, agar, stearic acid and sodium, calcium and magnesium stearates.

The pharmaceutical compositions of the invention may also contain other non-toxic adjuvants and modifiers such as dyes, surfactants, perfumes, flavoring agents, preservatives and biocides.

The pharmaceutical composition of the invention preferably contains 10 to 90 wt. percent of N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide or salt thereof. The preferred forms for oral administration preferably contain 20 to 80 wt. percent.

A preferred formulation for an orally administrable pharmaceutical composition according to the invention is the following N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 20-80% Disintegrating agent or decomposition accelerator, e.g. maize- or wheat-starch 10-20% Binding Agent e.g. gelatin, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, etc. (in many cases a part of the starch also can be pasted and added as binding agent, 5-10%). 0.5-3% Lubricant (Glidans) e.g. talcum, polyethylene glycol, colloidal silicic acid. 3-5% Lubricant (Lubricans) e.g. stearic acid, magnesium stearate. 0.1-2% Filler e.g. lactose, mannitol, calcium sulphate, sec. calcium phosphate. to 100%

The lubricant (glidans) reduces the friction between the particles of the powder and the granulate, and the lubricant (lubricans) reduces the friction between the instruments (punches, dies, etc.) used to form the composition into tablets and the like, and the composition. The lubricant (lubricans) also prevents the composition sticking to the instruments).

This composition may for example be made up as plain or delayed-release tablets or dragees or filled into capsules.

The present invention also provides antihyperglycaemic medicaments in dosage unit form as hereinafter defined comprising N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide or a non-toxic salt thereof either alone or in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier. In this case the diluent or carrier is preferably as defined above but can also be water or another common solvent.

The expression "medicament in dosage unit form" as used in the present specification means a medicament in the form of discrete portions each containing a unit dose or a multiple or sub-multiple of a unit dose of the active ingredient(s); for example, one, two, three, or four unit doses or a half, a third or a quarter of a unit dose. A "unit dose" is the amount of the active ingredient(s) to be administered on one occasion and will usually be a daily dose, or for example a half, a third, or a quarter of a daily dose depending on whether the medicament is to be administered once or, for example, twice, three times, or four times a day.

The discrete portions constituting the medicament in dosage unit form can include a protective envelope. The active ingredient can be undiluted and contained in such an envelope, or can be mixed with a pharmaceutically acceptable solid or liquid diluent or carrier as defined above. Such portions can for example be in monolithic coherent form, such as tablets, pills, suppositories, or dragees; in wrapped or concealed form, the active ingredients being within a protective envelope, such as wrapped powders, cachets, sachets, capsules, or ampoules; or in the form of a sterile solution suitable for parenteral injection, such as ampoules of buffered, isotonic, sterile, pyrogen-free aqueous solution; or in any other form known in the art.

As stated above, it is preferred to administer N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide and its salts perorally. Preferred medicaments in dosage unit form according to the invention are therefore those adapted for oral administration, such as tablets, pills, dragees, capsules, and cachets, as well as wrapped powders containing the active ingredient in powdered form with a powdered diluent or carrier for suspension in water before being taken.

The preferred unit dose for administration of the medicaments of the invention is 5-100 mg. of N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide or salt thereof. This will normally be administered one to five times daily. In the preferred medicament for oral administration the preferred unit dose is also 5-100 mg. One discrete portion of the medicament preferably contains about 30 mg. of N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide or salt thereof.

The invention further provides a method of depressing the blood sugar level in an animal which comprises administering to the animal (preferably perorally) a pharmaceutical composition according to the invention or a medicament in dosage unit form according to the invention.

Since the antidiabetic effect of the commercial biguanides occurs only with high doses, permanent treatment involves the risk of intolerance [cf. H. Mehnert and H.S. Sadow in "Oral Hypoglycaemic Agents," page 281, Academic Press London, 1969]. The use according to the invention of N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide and its non-toxic salts as anti-hyperglycaemic agents having a far lower toxicity but effective in substantially smaller doses therefore constitutes an important advantage.

The preparation of this compound is known [F.H.S. Curd, J.A. Hendry, T.S. Kenny, A.G. Murray and F.L. Rose, Soc. 1946, 729].

The antihyperglycaemic effect can be demonstrated by the following experiment:

After several oral administrations of the active ingredient, fasted rats are given glucose dissolved in a physiological sodium chloride solution per os. The blood glucose level of the animals treated with an effective biguanide rises to a smaller extent, dependent upon the size of the dose, than that of untreated animals. Measuring takes place 30 and/or 60 minutes after application of the glucose. The stated dose is in each case the individual dose which, compared with the untreated control animals, causes a significant (P < 0.05) reduction of hyperglycaemia after application of glucose. (P. = probability of error). R m.p. of Dose LD.sub.50 hydrochloride (Rat) (Rat) in mg/kg _________________________________________________________________________ _ H 238-239.degree.C 2.5 589 4-Cl* 250-251.degree.C 10 114 _________________________________________________________________________ _

FOOTNOTE: *the known Proguanil hydrochloride.

Our copending patent application Ser. No. 118,958 Le A 12 829 - A discloses and claims the pharmaceutical use of certain other N.sup.1 -aryl-N.sup.5 -alkyl-biguanides as antihyperglycaemic agents.

Our copending patent application Ser. No. 120,332 Le A 12 829-A discloses and claims certain new N.sup.1 -aryl-N.sup.5 alkyl-biguanides and their use as antihyperglycaemic agents.

The following examples illustrate the pharmaceutical compositions and medicaments of the invention. It is to be understood that though the examples mention only the free biguanide, an equivalent amount of any of its non-toxic salts can equally well be used. Example 1: Tablets a) Per tablet: N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 30 mg. Lactose 99 mg. Maize starch 60 mg. (of which 15 mg. as paste) Talcum 10 mg. Magnesium stearate 1 mg. _________________________________________________________________________ _ Total 200 mg. _________________________________________________________________________ _

The biguanide, the lactose and half the quantity of maize starch are mixed, kneaded together with a paste of one quarter of the quantity of maize starch, pressed through a sieve with 3-5 mm. mesh size, and dried in a suitable drier at 60.degree.-80.degree. C. The dry granulate is forced through a sieve with 0.8 mm. mesh size, and the remaining quarter of the maize starch as well as the talcum and magnesium stearate are mixed in. The resultant composition is pressed into round tablets of 8 mm. diameter and a total weight of 200 mg. with the help of an ordinary tablet press. b) Per tablet: N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 30 mg. Sec. Calcium phosphate 97 mg. Gelatin 2 mg. Wheat starch 20 mg. Magnesium stearate 1 mg. _________________________________________________________________________ _ Total 150 mg. _________________________________________________________________________ _

The biguanide and sec. calcium phosphate are mixed, kneaded with an aqueous solution of gelatin, sieved (3-5 mm) and dried (60.degree.-80.degree. C). The dry granulate is sieved (0.8 mm). Finally the wheat starch and magnesium stearate are mixed in and the resultant composition formed into tablets in known manner (round tablets, diameter 7 mm., gross tablet weight 150 mg). Example 2: Delayed release tablets a) Two-layer dragee. N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 15 mg. Sec. calcium phosphate 82 mg. Gelatin 2 mg. Wheat starch 20 mg. Magnesium stearate 1 mg. _________________________________________________________________________ _ Total 120 mg. _________________________________________________________________________ _

These ingredients are compounded as in Example 1(b) into round, suitably curved tablets 6.5 mm. in diameter. Lacquering: The nuclei are lacquered with a 10 percent solution of cellulose acetate phthalate (with some castor oil or diethylphthalate as plasticizer) in known manner until the nuclei satisfy the specifications of the pharmacopeia for resistance to gastic guice. Sugar coating: The lacquered nuclei are next coated in known manner with the following suspension until the applied layer contains 15 mg. biguanide per dragee: N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 20% Sugar 40% Gum arabic 1% Gelatin 0.1% Talcum 10% Water ad 100%

After the further addition of a few layers of a suspension of: Sugar 60% Gum arabic 1% Gelatin 0.1% Talcum 10% Water ad 100% the dragees are completed to the required final weight with a 60 percent solution of sugar syrup in known manner.

Some edible dye can be added to the syrup at this point.

Finally, the dragees are glazed (polished) with a suitable glazing wax.

These dragees release the first half of the active ingredient immediately in the stomach, but the second half only in the intestine. b) Wax-matrix tablets Per tablet; N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 30 mg. Hydrogenated castor oil 60 mg. Glycerin monostearate 10 mg. _________________________________________________________________________ _ Total 100 mg. _________________________________________________________________________ _

The hydrogenated castor oil and the glycerin monostearate are melted together. The biguanide is homogeneously suspended in the melt. Finally, the melt is poured out into plates and solidified. It is then pulverized to a particle size of 0.5 mm. The resultant powder is formed with a suitable tablet-press into tablets with a diameter of 6 mm. The tablets release the active ingredient in the intestinal tract continuously inside 4-6 hours for

The above mentioned melt can also be converted to a powder capable of formation into tablets by spray-solidification in a spraying tower. Example 3: Capsules

a) Per capsule: N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 30 mg. Sec. calcium phosphate 116 mg. Magnesium stearate 3 mg. Colloidal silicic acid 1 mg. _________________________________________________________________________ _ Total 150 mg. _________________________________________________________________________ _

The ingredients are mixed and filled into hard gelatin capsules with a suitable capsule filling and closing machine. b) Per capsule: N.sup.1 -phenyl-N.sup.5 -isopropyl biguanide 30 mg. Lactose 60 mg. Polyvinylpyrrolidone 3 mg. Stearic acid 1 mg. Colloidal silicic acid 1 mg. Talcum 5 mg. _________________________________________________________________________ _ Total 100 mg. _________________________________________________________________________ _

The biguanide and lactose are mixed, kneaded with a solution of polyvinylpyrrolidone and stearic acid in methylene chloride, sieved (3-5 mm) and dried (50.degree.-60.degree. C).

The dry granulate is forced through a sieve with mesh width of 0.5-0.6 mm. The colloidal silicic acid and talcum are mixed in, and the resultant composition is filled with a suitable apparatus into hard gelatin capsules.

c. Further, the wax granulate described under 2(b) can, instead of being tabletted, also be filled into hard gelatin capsules. Capsules with delayed release of active ingredient are then obtained.

Claims

1. A method of depressing the blood sugar level of a hyperglycaemic animal comprising administering to the animal an antihyperglycaemic amount of N.sup.1 -phenyl-N.sup.5 -isopropyl-biguanide or a nontoxic salt thereof.

2. A method according to claim 1 in which the administration is carried out perorally.