KR0128663B1 - Topically applied gold okganic complex - Google Patents

Abstract

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Description

Topically applied gold organic compounds

The present invention relates to a pharmaceutical composition of a gold compound applied topically and its use as a psoriasis treatment and an antifungal agent.

background

Elemental gold has long been believed to have many healing powers. However, in the 1960s, it was proved to be effective in the treatment of simple inorganic gold salt rheumatoid arthritis administered intravenously. Subsequently, aurothio maleate and aurothio glucose administered in parenteral form were found to be more effective. These are water soluble complexes with thiolate ligands containing almost 50% by weight of gold. Gold thiopolypeptides have also been injected. Auranopine, a lipid soluble complex compound containing about 29% by weight of gold and having a phosphine and a sulfur mate, has been administered orally.

Thus, gold compounds (the term is used herein to encompass one or more ligands, organo-gold compounds, inorganic gold compounds, and complex compounds that chelate or bind gold to salts thereof until now) parenteral. Only oral routes have been administered for therapeutic purposes and for the purpose of treating asthma, tuberculosis, vulgaris, various forms of arthritis, cancer and infections.

However, although different chemical forms of gold are recognized as having various effects in the treatment of the disease, despite the established clinical effects, the mechanism of action of gold compounds in the treatment of these conditions is unknown.

Gold is in oxidation states I and III,

Is a transition metal that can form complexes.

The chemistry of gold compounds is complicated by the tendency for many compounds to form composite polymers.

Another complexity is that gold compounds may undergo extensive modifications in the body, leading to active compounds.

Finally, there seems to be no correlation between the levels of various gold compounds in the blood and their biological activity.

The biological activity of gold compounds is not determined solely by the presence of gold itself, but depends on the following factors:

a. Oxidation state (I or III)

b. Degree of polymerization

c. Form of the ligand

d. Stereointegration of Molecules

The mechanisms proposed for the operation of gold drugs include:

a. Regulation of humoral immunity and cell-mediated immunity

b. Inhibition of the transporter released as a result of immune complex formation and / or immune complex formation

c. Inhibition of Formation and / or Release of Lysosomal Enzymes

d. Inhibition of Formation and / or Action of Prostaglandins

e. Inhibition of proliferation of synovial membranes and other cell types, including cancer cells

f. Regulation of copper and zinc metabolism

g. Enzyme inhibition

Oranopine administered orally showed prolonged blood levels of gold compared to parenteral administered gold compounds and remained minimal in tissues. Parenteral and oral routes of administration are known to cause severe side effects in many cases, including skin and mucosal lesions, as well as in the kidney and blood in some cases. Often, oral gold can cause severe gastrointestinal upset.

In particular, the synovial membrane is known to selectively absorb gold initially injected or orally and then distributed to other tissues when inflammation occurs.

An example of selective activity is shown by auranophine, which has a greater affinity for infiltration of lymphocytes than many other gold compounds, especially those of hydrophilic type.

In 1984, Brown Copper applied water-soluble and fat-soluble gold compounds as ethanol solutions to the skin of rats to determine the level of gold absorbed into the bloodstream through topical application. DH Brown et al., Inorganica Chimica Acta, 93 , L41-L42 (1984)]. As a result, the water-soluble complex was absorbed more rapidly in the blood than the water-soluble complex, and the degree of absorption in the blood was similar to that of oral administration. However, no corresponding experiments have been reported with respect to human skin, and no studies have shown a correlation between the blood levels of gold and the clinical effects of the aforementioned treatments for mice or human diseases.

Surprisingly, it has now been found that topically administered gold compounds are significantly more effective than parenteral or oral routed gold compounds, in some circumstances, while avoiding or alleviating the side effects discussed above.

It has also been surprisingly found that topically administered gold compounds are effective in the treatment of local and systemic inflammatory conditions such as psoriasis and rheumatoid arthritis and / or as antifungal agents.

Locally applied gold compounds are known to act synergistically with corticosteroids in the treatment of local inflammatory conditions, especially psoriasis.

Summary of the Invention

Therefore, the present invention, in one aspect, relates to the use of topical application of gold compounds (as defined above) for the treatment of local and systemic inflammatory conditions, in particular psoriasis and rheumatoid arthritis.

In a second aspect, the present invention relates to a topical composition comprising a mixture of gold compounds with a pharmaceutically acceptable carrier having a viscosity greater than water.

In a third aspect, the present invention relates to a method of treating an infected site of an infected patient, comprising applying a gold compound to or near the inflamed skin.

Preferably, the gold compounds used in the present invention are fat soluble.

In a preferred embodiment, the present invention relates to a synergistic mixture of gold compounds and corticosteroids.

The combination of gold compounds and corticosteroids has been surprisingly found to increase the therapeutic effect and reduce side effects.

Surprisingly, they also found that gold compounds are effective against pathogenic bacteria, including gram-negative and gram-positive bacteria, and particularly against gram-positive bacteria.

Best Practice

The present invention more specifically describes certain embodiments using examples.

The best gold compound in use is hydrophilic, representative of type R ₃ P-AU-C1 (wherein R is methyl, ethyl, iso-propyl or n-butyl); Type R ₃ P-AU-SR '[(wherein R is alkyl, alkoxyl or phenyl, R' is H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted, and a preferred R 'residue is Substituted carbohydrates and

(Wherein R is alkyl or hydrogen); and type

Wherein R is a gold phosphine compound, all of which may be the same or different, may be alkyl, aryl or heterocyclic, and may be substituted or unsubstituted. An example clinically used is auranofin of the structure:

Preferred compounds for use in the present invention include gold (I) phosphine and related compounds, gold (I) phosphine (or phosphite) thiolates, bis-coordinated gold (I) salts and gold (I) chelates. Include.

As a preferred embodiment of the present invention, the most preferred corticosteroid used with the gold compound is betamethasone dipropionate. However, other corticosteroids may be the same in effect.

Pharmaceutical preparations

Pharmaceutical preparations suitable for the application of gold compounds to the skin include solutions, powders, gels, ointments, creams, sprays (including measured aerosol sprays), and patches. The choice of formulation depends on the therapeutic use to be attempted.

The choice of agent for topical use depends on the type and location of the lesion. The formulations may also include stabilizers and / or penetrants. Although hydrophobic emulsified softwoods give satisfactory results for general topical use, any other topical formulation may be used equally, such as monovalent, divalent, and alkanols. The alcohols may be short chain (C ₁ to C ₁₀ ) alcohols or long chain (C ₁₂ to C ₂₀ ) alcohols.

Especially preferred are polyhydric alcohols such as diethylene glycol and glycerol. Simple hydrocarbon substrates are also effective.

The compounds according to the invention are believed to be effective in reducing the symptoms of inflammatory diseases when applied topically to humans and animals. The composition is believed to be effective at relatively low concentrations and so side effects are minimized compared to other gold administration methods.

Moreover, the preparations prepared according to the invention may often comprise a keratolytic substance, more preferably salicylic acid. As another strategy, ointments containing heparinoids and hyaluronic acid enzymes may promote the absorption of auranopine.

Preferably, the base ointment is a wool alcohol ointment or a simple hydrocarbon base.

Formulation of auranopine ointment

ingredient

Ridura (Auranopine) tablets (3mg)

Alcohol (90%) ... 20m1

Propylene Glycol ... 5m1

Ointment of wool alcohol up to 100 g

Produce

The lidaura tablets are ground in glass smoke and alcohol is added. It was soaked in water for 15 minutes, ground for 15 minutes and most of the alcohol was evaporated until then. Propylene glycol was added and the mixture was ground again for 10 minutes. The ingredients in the drug product were weighed and an ointment of wool alcohol was added to this weight.

It is expected that commercially prepared aurapine ointments should be prepared from pure auranopine powder, not tablets.

Another preferred method of preparing the ointment is to grind the aurapine powder with mineral oil, vegetable oil or fish oil. Then add the meat. The meat products may be pure hydrocarbon based or contain emulsifiers such as wool alcohol.

Formulations containing topical medications are well recognized to affect clinical efficacy. The addition of adjuvant such as propylene glycol and urea may promote the amount of active agent penetrating the skin.

In inflammatory skin diseases, the absorption barrier collapses to allow significant systemic absorption of the drug, which is not normally absorbed into the percutaneously. In other dermatological conditions, violent abortion or thyroiditis may interfere with topical penetration of the drug. A similar phenomenon occurs when the symptoms occur in the palms or soles of the feet. In such cases, keratin solubilizers may be needed if the drug can reach the site of action of the skin by adding it to the formulation or using it prior to treatment with the active drug.

The formulations may vary depending on the condition and location of the psoriasis lesion. Oily preparations such as those mentioned above are not suitable for use on the scalp. Thus the formulations may be varied as desired by those skilled in the art.

Example 2

Other formulations

Propylene glycol ・ ・ ・ ・ ・ 10m1

Auranofin ... 1.8 g / g

Lasonil ^R ointment ········· 14 g

Diprosone ^R ointment ············ l5g

Wool alcohol ointment ... up to 90 g

The final concentration of betamethasone dipropionate in this formulation is about 0.008%.

Only compositions containing auranopine are exemplified here, but suggest that equivalent compositions containing any of the following gold compounds may be equally effective.

LASONIL is a Bayer trademark and contains 5,000 HDBY heparinoids and 15,000 units of hyaluronic acid degrading enzyme per 100 g ointment.

DIPROSONE is a Schering trademark and contains 0.05% betamethasone as dipropionate.

Example 3

Preferred gold (I) phosphines and related compounds thereof are represented by the general formula (I):

R ₃ PAUX (I)

Wherein R is alkyl, aryl or heterocyclic and may also be substituted; X is halogen.

Preferred examples are Et ₃ PAuCl and Ph ₃ PAuCl, where Ph is phenyl and Et is ethyl.

The compound of formula (I) may be prepared by reacting HAuX ₄ (1 mol) with an ethanol solution of R ₃ P (2 mol) or by reacting AuX with PR ₃ . Compounds prepared by this method have high fat solubility.

Related compounds useful in the practice of the present invention include trialkylphosphites of formula (Ia) and thiocyanate complexes of formulas (Ib) and (Ic);

(RO) ₃ PAuX (Ia)

R ₃ PAuSCN (Ib)

(RO) ₃ PAuSCN (IC)

Wherein R and X are as defined above. R is preferably ethyl or phenyl.

Example 4

Preferred gold (I) phosphine (or phosphite) thiolates of the invention are represented by the following general formula (II):

R ₃ PAuSR ¹ (II)

Wherein R and R ¹ may be H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted. Preferred examples include compounds wherein R is ethyl or phenyl and R ¹ is a substituted carbohydrate moiety and consequently the following compounds:

Wherein X is hydrogen, acetyl or formyl; Y is O or S; n is 1 to 12. Another preferred example of this type of compound is a compound of the formula:

The following are examples of preferred synthetic routes used to prepare these compounds:

R ₃ P + AuC1 → R ₃ PAuCl

_{^{R 3 PAuCl + R 1 S -}} → R 3 PAuSR 1 + C1 -

Examples of other suitable compounds include thioalcohols (eg R ₃ PAuSCH (R ¹ ) CH (R ² ) OR ³ ), thioacids (eg R ³ PAuSCH (R ¹ ) CH (R ² ) COOR ³ ), thiophenols (eg Phosphine or phosphite Au (including derivatives of R ₃ PAuSC ₆ H ₄ R ² ), wherein R ¹ , R ² , R ³ = H, alkyl, aryl or heterocyclic and may or may not be substituted; I) complexes. In the case of thiophenols R ² can be any group, for example NH ₂ .

Another example of a suitable compound in this case includes R ₃ PAuX, wherein X is a residue such as 2-thiazolinyl, thio-2-benzimazolyl and 2-benzoxazolylthio. Cyclocyclic chelate compounds such as the following general formula (IId) are also suitable compounds.

Wherein R = H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted. Also suitable are (R ₃ PAu) ₂ S.

Example 5

Preferred bis-coordinating gold (I) salts are represented by the general formula:

[R ₃ PAuPR ₃ ] ⁺ X- (IIIa)

[R ₂ SAuSR ₂ ] ⁺ X- (IIIb)

[RC ₅ H ₄ NAuNC ₅ H ₄ R] ⁺ X- (IIIc)

[R ₃ PAuNC ₅ H ₄ R] ⁺ X- (IIId)

Wherein R is alkyl, aryl or heterocyclic and may be substituted or unsubstituted; X is a halide, C10 _{4 '} BF ₄ or a monovalent or divalent anion known in the art.

Example 6

Preferred gold (I) chelates are represented by the following general formula (IV):

Wherein R is a suitable bridge moiety and is substituted or unsubstituted alkyl, aryl or heterocyclic; X is O, N or SO ₂ NR ₂ and R ¹ is H, alkyl, aryl or heterocyclic and may be substituted or unsubstituted.

Preferred examples are those wherein R is C ₆ H ₄ , X is 0 and R 'is C ₂ H ₅ .

Example 7

A basic study of 19 psoriasis patients showed significant therapeutic effects and extremely limited side effects.

One patient is a middle-aged man who has suffered from severe psoriasis for a long time due to poor healing with conventional treatment. Under the prescription of a dermatologist, auranopine ointment (1.8 mg / g) was applied to the large area of the patient's back as well as to the small area of the left leg. Placebo ointment was applied to the cheeks of the face and the right leg of the small area. The patient was not sure which ointment was active and which ointment was a placebo. Over a week I applied 80g of ointment, equivalent to 144mg of auranopine.

At the end of the first week it was observed that the patient's condition improved markedly in terms of the area treated with the active drug. The patient and the dermatologist had no objection to the superior therapeutic effects achieved during the same treatment period by other therapies used previously. The placebo-treated skin did not improve and only worsened during the first week.

The patient was then treated with reduced ointment but the condition continued to improve.

Another patient treated with auranoffin ointment suffered from mild psoriasis. The patient applied ointment to a small patch of psoriasis and after 3 days the site was found to be markedly isolated. Similar benefit was obtained from the other 17 patients.

The choice of topical preparation is determined by the shape and location of the lesion. The formulation may contain stabilizers and / or penetration agents. For general topical use, the use of hydrophobic emulsified meat products will produce satisfactory results. However, likewise monovalent, divalent and trivalent alkanols can also be used in topical formulations. The alcohol may be a short chain (C ₁ to C ₁₀ ) alcohol or a long chain (C ₁₂ to C ₂₀ ) alcohol.

Especially preferred are polyhydric alcohols such as diethylene glycol or glycerol.

Topical auranofin products should be used in at least 0.2% and 0.1%. Additional therapeutics may be needed to achieve maximum efficacy. For example, it may be necessary to pre-apply keratinous dissolution if there is severe deterioration.

In light of the evidence for synergistic effects between auranopine and corticosteroids, it may be appropriate to use all of these agents simultaneously in sequence. In addition, the aurapine applied to the skin lasts for a period of time after the drug is discontinued, so that the synergistic effect between the steroid and the auranopine is expected to continue after the auranopine is stopped.

Auranopine has properties that, if properly formulated, can be highly desirable topical drugs. It is not only very effective, but also cosmetically suitable and much easier and more comfortable to use than many conventional therapies. Also, based on a limited number of patients, auranofin is not likely to cause any side effects, but its latent risk is much less than other potent psoriasis treatments such as methotrexate and etretinate. Can be. In addition, the therapeutic effect of auranopine is superior to methotrexate and etredinate. Corticosteroids can be very effective in treating psoriasis, but the continued use of the drug in some patients can cause systemic side effects of gastric atrophy and damaged skin.

As will be apparent to those skilled in the art, other gold compounds other than those exemplified herein may be selected based on their fat solubility and such compounds are included within the scope of the invention when contained in topical formulations.

Claims (11)

A pharmaceutical composition for topical treatment of an inflammatory or immune disease containing a fat soluble oil-based compound and a pharmaceutically acceptable carrier having a viscosity greater than that of water. The composition according to claim 1, wherein the gold organic compound is in an oxidized state. The composition according to claim 2, wherein the gold-based complex compound is represented by the following general formula.

Wherein X is H, acetyl or fryl, A is -S-Au-PR ₃ or -Y- (CH ₂ ) nS-AuPR ₃ , where R is H, alkyl, aryl or heterocyclic and substituted Or unsubstituted); Y is 0 or S; n is 1 to 12. The composition of claim 3 wherein the gold complex is represented by a structural formula:

The composition according to any one of claims 1 and 2 to 4, further comprising a corticosteroid. The composition of claim 5 wherein the corticosteroid is betamethasone dipropionate. A pharmaceutical composition for topical treatment of inflammatory or immune diseases, comprising a betamethasone dipropionate and a pharmaceutically acceptable carrier, represented by the following general formula:

Wherein X is H, acetyl or formyl; A is -S-Au-PR ₃ or -Y- (CH ₂ ) nS-AuPR ₃ , wherein R is H, alkyl, aryl or heterocycle, which may be substituted or unsubstituted; Y is O or S; n is 1 to 12. The pharmaceutical composition according to claim 7, wherein the gold-based complex compound is represented by another structural formula.

The pharmaceutical composition according to claim 8, wherein the concentration of the gold compound is 0.05 to 0.25% by weight of the total composition. The composition of claim 7, wherein the carrier is an ointment. The pharmaceutical composition of claim 1 wherein the inflammatory condition is psoriasis.