WO1993015752A1

WO1993015752A1 - Anti-neuropathic composition

Info

Publication number: WO1993015752A1
Application number: PCT/EP1993/000345
Authority: WO
Inventors: Cornelis Martinus Groenhout
Original assignee: Akzo N.V.
Priority date: 1992-02-17
Filing date: 1993-02-12
Publication date: 1993-08-19
Also published as: AU3497093A

Abstract

Disclosed are pharmaceutical preparations and drug delivery systems containing pharmaceutically effective amounts of an aldose reductase inhibitor and a hexapeptide of the formula: H-Met(X)-Glu-His-Phe-D-Lys-Phe-Y wherein Met(X) represents the amino acid derivative Met(O) or Met(O2), and Y represents the group Gly-Z or Z, with Z representing the hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group. The preparations are useful in the treatment and prevention of diabetic neuropathies.

Description

Anti-neuropathic Composition

_A — Te—ch—ni^c——al———Fi—el^d— This invention relates to a preparation for the treatment and/or prevention of 5 diabetic neuropathies.

Background Art: One complication associated with diabetes mellitus is the development of neuropathies. Diabetic neuropathies are heterogeneous with the major

10 clinical problems being tissue damage, pain and neuropathic foot ulcerations. Masson and Boulton, "Aldose Reductase Inhibitors in Diabetic Neuropathy", Druαs. 39(2): 190 - 201 (1990).

The metabolic "polyol pathway" has been theorized

15 to be a cause of diabetic neuropathies. The polyol pathway is a metabolic pathway used by mammals to convert glucose into fructose by way of a sorbitol intermediate. This conversion is catalyzed by the enzyme aldose reductase. Evidence for this theory is

20 supported by the fact that aldose reductase is found in target tissues associated with diabetic complications. Id.

Because of the plausibility of the theory, attempts have been made to treat people suffering with diabetic

25 neuropathies by the use of aldose reductase inhibitors, such as alrestatin, sorbinil, tolrestat, ONO-2235 (epalrestat) , statil, and ponalrestat. Unfortunately the results with such treatments to date have not proven to be as successful as hoped for. Id.

30 Another proposed treatment for preventing or combating diabetic neuropathies includes the

" administration of the compound Org 2766. See, e.g. EP-

Bl-0 303 308 to AKZO, N.V. and van der Zee et al,

"Beneficial effect of the peptide Org 2766 (ACTH-(4-9)

35 analog) in the treatment of peripheral neuropathy in streptozocin-diabetic rats", Diabetes, 38: 225-230 (1989) .

Org 2766 is a hexapeptide of the formula: H-MetO_i-Glu-His-Phe-D-Lys-Phe-OH and is described in U.S. Patent No. 3,842,064 (as used herein, "Met0₂" is methionylsulfone; "Glu" is glutamyl; "His" is histidyl; "Phe" is phenylalanyl; and "D-Lys" is D-lysyl, if no special optical configuration is stated, then the L-form is intended) . This patent and others (e.g. U.S. Patent Nos. 4,550,099, 4,104,371, and 4,110,322) disclose methods of producing this and similar polypeptides.

The mechanism of action for Org 2766 has not yet been specifically determined, however, it is believed to be a neurotrophic factor having a regenerative effect on the nervous system.

Disclosure of the Invention.

Surprisingly, it is found that by treating diabetes with pharmaceutically effective amounts of both an aldose reductase inhibitor and Org 2766, a synergism is created with the combination having greater efficacy than the sum of its components.

The invention thus includes a drug delivery system containing both an aldose reductase inhibitor and a hexapeptide compound of the formula:

H-Met(X)-Glu-Hiε-Phe-D-Lys-Phe-Y wherein Met(X) represents the amino acid derivative Met(O) or Met(0₂), and Y represents the group Gly-Z or Z, with Z representing the hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group. The invention also includes processes for manufacturing and using the pharmaceutical preparation.

Best Mode of the Invention

I. The Hexapeptide-

Although the hexapeptides may be prepared by other methods known for the preparation of analogous compounds (e.g. by use of a solid phase synthesis), a method of making the hexapeptides, and especially the most preferred hexapeptide Org 2766 (i.e. H-Met0₂-Glu-His- Phe-D-Lys-Phe-OH) , is described in U.S. Patent No. 3,842,064, the entire contents of which are incorporated by this reference. See e.g., column 3, line 6 to column 6, line 15; column 7, line 1 to column 15, line 15; and EXAMPLE XI of U.S. Patent No. 3,842,064.

Preferably, the hexapeptide used with the invention will have Met(0₂) (methioninesulphone) as Met(X), and Y will be a hydroxyl group, a hydroxyl group which is esterified with an aliphatic alcohol having 1 to 18 carbon atoms (preferably 1 to 6 carbon atoms) or a substituted group of the type -NH-ALK-NH₂ wherein ALK represents an alkylene group with two to ten carbon atoms, preferably 4 to 10, and more preferably 7 or 8 carbon atoms.

N-acyl derivatives of the hexapeptides refer to hexapeptides which are acylated at the N-terminal side with a lower ( C±-₈ ) aliphatic monocarboxylic acid or dicarboxylic acid, such as acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, or glutaric acid.

However made, the hexapeptides form pharmacologi¬ cally acceptable salts from pharmacologically acceptable organic and inorganic acids such as hydrochloric, hydro- bromic, fumaric, phosphoric, ascorbic, tartaric, citric, lactic, maleic, palmitic, and other well-known acids. Especially preferred are the hydrochloric and acetic acid salts. The acid addition salts are obtaineu by reacting the hexapeptide with the acid. As used herein, the use of the hexapeptide includes the use of its salts or N-acyl derivatives.

Methods of making crystalline hexapeptide are disclosed in EP-A-0 461 696 to AKZO, N.V. The dosage of hexapeptide according to the general formula administered will generally be dependent upon the type of patient involved, his age, health, weight, kind of concurrent treatment, if any, and length and frequency of treatment. Administered parenterally, the amount of such a hexapeptide in a pharmaceutical preparation (e.g. a solution for injection) varies from 10^"4 to 2 X 10~² mmol per ml and more especially between 0.4 X 10^~3 to 7.5 X 10^~3 mmol per ml.

An outstandingly suitable injection preparation according to the invention contains between 0.35 and 6.5 mg of the hexapeptide 2766 per milliliter preparation.

Illustratively, dosage levels of crystalline hexapeptide (Org 2766) can be (intranasally) between 0.55 mg and 27 mg per day. In human therapy, daily doses of between 8 mg and 25 mg, administered intranasally, will preferably be used. A nasal liquid spray containing the hexapeptide will contain similar dosages.

II. The Aldose Reductase Inhibitor-

Tolrestat is an aldose reductase inhibitor marketed by Wyeth Laboratories of Berkshire, UK under the trade designation "Alredase". A pharmaceutically effective amount of tolrestat is 200 to 400 mg administered orally. The compound is described in U.S. Patent Nos. 4,716,177 and 4,701,467, both to Ryder et al.

Another aldose reductase inhibitor is (+)6-fluoro- spiro[chroman-4,4'-iraidazolidine]-2' ,5'-dione ("sorbin- il", Pfizer, Sandwich, Kent, UK). A pharmaceutically effective amount of sorbinil is 250 mg per day.

Alrestatin is 1,3-dioxo-lH-benz-deisoquinoline- 2(3H)-acetic acid (Wyeth - Ayerst Laboratories, NYC, NY).

Other aldose reductase inhibitors and there usual useful dosages are known, such as ONO-2235, statil, and ponalrestat.

III. Pharmaceutical Compositions-

Once the hexapeptide has been made, it can be used in conjunction with the aldose reductase inhibitor to make to make a pharmaceutical preparation according to the invention. Such a pharmaceutical preparation may contain both the aldose reductase inhibitor and the hexapeptide, e.g. in a solution or suspension for injection. It may also contain separate pharmaceutical compositions, one containing the aldose reductase inhibitor and the other containing the hexapeptide.

In its simplest form a pharmaceutical composition for the hexapeptide contains merely the hexapeptide (e.g. crystalline Org 2766) itself, e.g. for nasal administration. The pharmaceutical compositions containing the hexapeptide are preferably dispensed in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions and non-parenteral solutions or suspensions, containing suitable quantities of a pharmaceutically acceptable salt of the hexapeptide.

The hexapeptide may also be incorporated into devices intended for implantation into a patient. Such devices, polymers intended for use therein, and methods of making both are described in U.S. Patent Nos. 3,773,919, 4,767,628, and 4,675,189. For example, a sufficient quantity of the crystalline hexapeptide could be incorporated into a PLAGA implant to allow for the release of hexapeptide (e.g. 5 mg per day for one month) into the patient's body.

Although the pharmaceutical compositions containing the hexapeptide may be formulated with adjuvants such as solubilizers or absorption enhancers, they need not be. Buffers, gelling agents, etc. may also be used in such formulations. Buffering agents are preferably those which keep the hexapeptide in its unionized form.

Pharmaceutical preparations containing the hexapeptide, especially those for parenteral administration may also contain antimicrobial substances such as methyl parahydroxybenzoate; substances for rendering the preparation according to the invention isotonic; substances which can adjust the pH of an aqueous solution to a value of between 4 and 7.8. The aldose reductase inhibitors may similarly be compounded to form the described pharmaceutical preparations, although the most preferred presentation form for the aldose reductase inhibitors is a capsule or tablet.

Methods and compositions for making dosage forms are well-known to those skilled in the art. For example, methods of making powders, and their compositions are described at pages 1535 through 1552 of the standard English language text Remington s Pharmaceutical Sciences. (16th ed. , Mack Publ. Co. Easton, PA, USA 1980). Insufflations are described at page 1552, and insufflators are described at 1792 of the same reference. Methods and compositions for making tablets and pills, containing active ingredients, are described in Remington 's . at pages 1553 through 1584. Methods of coating pharmaceutical dosage forms, and making prolonged release pharmaceuticals are described at pages 1585-1613 of Remington 's. In one embodiment of the invention, the aldose reductase inhibitor and hexapeptide are incorporated into a solution or suspension for subcutaneous injection. The injection liquid then contains sufficient amounts of both drugs to be pharmaceutically effective.

A drug delivery system according to the invention is basically a "kit of parts" containing the described therapeutic agents. The therapeutic agents are then packaged or dispensed together for concomitant use. This drug delivery system thus has use in the treatment or prevention of diabetic neuropathies in mammals, especially humans.

In a preferred drug delivery system according to the invention, the different dosage forms (e.g. tablets containing the selected aldose reductase inhibitor and vials containing unit doses of the hexapeptide) are arranged in a package so that the tablets and the hexapeptide containing vials are administered one after another, thus informing the patient what dosage forms have been taken. The package may have a calendar scheme

* to further help the patient. The dosage units are thus in fact arranged relatively to each another so that the

* 5 required operation results from normal use.

Preferred drug delivery systems according to the invention include 10 to 100 first daily dosage units, each containing a pharmaceutically effective amount of aldose reductase inhibitor, and at least one second

10 dosage unit containing the hexapeptide. In the case where there are for example 30 separate dosage units, each will contain a pharmaceutically effective amount of the hexapeptide based on daily administration cycle. When there is one second dosage unit in the drug

15 delivery system, it will preferably contain enough hexapeptide to be administered on a daily basis for as many days as there are first dosage units in the drug delivery system.

20 V. Administration-

The dosage forms will generally be administered over the life of the patient.

To prevent the occurrence of neuropathies the compounds are administered to a diabetic believed to be

25 susceptible to suffering from neuropathies some time in the future. The compound may need to be administered for the person's lifetime.

A method of treating or preventing diabetic neuropathies in a patient using the pharmaceutical 30 composition or drug delivery system comprises: daily administering a pharmaceutically effective amount

^* of an aldose reductase inhibitor to the patient, and also daily administering to the patient a pharmaceutically effective amount of a compound of the

35 formula:

H-Met0₂-Glu-His-Phe-D-Lys-Phe-OH. While not intending to be bound by one theory of the invention, the following explanation may help to explain it further. Since Org 2766 is thought to have a regenerative effect on nervous tissue, should a static situation exist in which a nerve is damaged, Org 2766 may enhance the natural nerve repair mechanisms and consequently may positively influence regeneration of nerve function. In situations such as diabetic neuropathy, the putative neuropathic agent (sorbitol) is still present, continuously damaging nerve fibers and myelin sheaths. In such a situation a disturbance may exist between degenerating effects and repair mechanisms resulting in neuropathy. By administering an aldose reductase inhibitor to patients with diabetes mellitus, the toxic internal environment can be influenced in such a way that toxic sorbitol levels at nerve tissue level decrease, although not to the degree desired. The Org 2766 might therefore act somehow to give an "extra boost" to the natural repair mechanisms resulting in a synergistic combination.

The invention is further explained by reference to the following illustrative examples.

EXAMPLE I

A. Preparation o the hexapeptide. The hexapeptide may be conveniently obtained by the methods described in U.S. Patent No. 3,842,064 in EXAMPLE XI

(1).

B. Pharmaceutical Solution. A solution containing the hexapeptide of EXAMPLE I.A. is prepared containing the following per milliliter:

Hexapeptide 3.0 mg

Methylparahydroxybenzoate 1.0 mg

Sodium acetate trihydrate 1.4 mg

NaCl 7 mg HC1 and NaOH to give a pH < 6.0 water for injection qsad 1 ml

The solution, intended for injection, is placed in a vial. C. Aldose Reductase Inhibitor. Tablets containing 200 mg of tolrestat may be purchased in Ireland under the trade designation "Alredase".

D. Drug Delivery System. 30 vials of EXAMPLE I.B. and put together with 30 tablets of EXAMPLE I.e.

A patient given the drug delivery system is instructed to administer one tablet and one vial daily.

EXAMPLE II

A similar drug delivery system as described in EXAMPLE I is prepared, but having under B a solution containing the hexapeptide of EXAMPLE I.A. containing the following per milliliter:

Hexapeptide 2.0 mg disodium monohydrogenphosphate 3.3 mg citric acid 2.85mg mannitol 35 mg water for injection qsad 1 ml

The solution, intended for injection, is placed in a vial.

Although the invention has been explained with the aid of various examples and embodiments, the extent of material claimed is to be determined by the claims.

Claims

Claims What is claimed is:

1. A pharmaceutical preparation comprising: a pharmaceutically effective amount of an aldose reductase inhibitor, in conjunction with a pharmaceutically effective amount of a hexapeptide of the formula:

H-Met(X)-Glu-His-Phe-D-Lys-Phe-Y wherein Met(X) represents the amino acid derivative

Met(O) or Met(0₂), and Y represents the group Gly-Z or Z, with Z representing the hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group.

2. The preparation of claim 1 wherein said aldose reductase inhibitor is selected from the group consisting of alrestatin, sorbinil, tolrestat, ONO- 2235, statil, ponalrestat, and mixtures thereof.

3. The preparation of claim 1 wherein said hexapeptide is a compound of the formula:

H-Met0₂-Glu-His-Phe-D-Lys-Phe-OH.

4. A drug delivery system comprising: first dosage units containing a pharmaceutically effective amount of an aldose reductase inhibitor ready for administration, and, at least one second dosage unit containing a pharmaceutically effective amount of a hexapeptide of the formula:

H-Met(X)-Glu-His-Phe-D-Lys-Phe-Y wherein Met(X) represents the amino acid derivative Met(O) or Met(0₂), and Y represents the group Gly-Z or Z, with Z representing the hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group.

5. The drug delivery system of claim 4 wherein said

=> aldose reductase inhibitor is selected from the group consisting of alrestatin, sorbinil, tolrestat, 0N0- S 5 2235, statil, ponalrestat, and mixtures thereof.

6. The drug delivery system of claim 4 wherein said hexapeptide is a compound of the formula:

H-Met0₂-Glu-His-Phe-D-Lys-Phe-OH. 10

7. The drug delivery system of claim 4 characterized in having the same number of second dosage units as first dosage units.

15 8. The drug delivery system of claim 7 further characterized in that all of said dosage units are arranged in a package containing the drug delivery system in such a manner that one first dosage unit and one second dosage are administered one after the

20 other on a daily basis.

9. The use of the drug delivery system of claim 4 in the treatment or prevention of diabetic neuropathies.

25 10. A process of manufacturing a drug delivery system comprising: associating pharmaceutical dosage units containing a pharmaceutically effective amount of an aldose reductase inhibitor with 30 at least one pharmaceutical dosage unit containing a pharmaceutically effective amount of a hexapeptide of the formula: ₄ H-Met(X)-Glu-His-Phe-D-Lys-Phe- wherein Met(X) represents the amino acid derivative 35 Met(O) or Met(0₂), and Y represents the group Gly-Z or Z, with Z representing the hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group.