DD150694A1 - METHOD FOR STABILIZING PHARMACEUTICAL PREPARATES WITH OXIDATING SENSITIVITIES - Google Patents

Abstract

The inventive method for the stabilization of pharmaceutical preparations with oxidation-sensitive components allows their industrial production by fulfilling the following tasks: first, significant extension d. Usability times, for epinephrine eye drops, for example, up to 3 years, second, the prevention of Verfaerbungs based on the formation of decayed decay products, third very good stability under extreme conditions during production, transport, storage and application and fourth, the possibility of storage at room temperature. The stabilization process is based on the combination of at least three pharmaceutical excipients - a Verfaerbungsprotektor, preferably sodium pyrosulfite, an antioxidant, preferably N-acetyl cysteine and the complexing agent diethylene triamine pentaessigsaeure. The mode of action is characterized in that each individual component influences different causes of the decomposition, each alone being only slightly effective, that the dual combinations of these components exhibit at most additive or synergistic activity enhancement and that the triple or multiple combination produces an over-additive stabilizing effect. This in turn is based on mutual stabilization or synergism of the individual components. The application is in the pharmaceutical field and has been tested for epinephrine eye drops as well as physostigmine eye drops and eye ointments.

Description

220475

Process for the stabilization of pharmaceutical preparations with oxidation-sensitive components

Field of application of the invention

The invention relates to a process for the stabilization of pharmaceutical preparations, whereby drugs or adjuvants which are sensitive to oxidative or induced disintegration can be stabilized in pharmaceutical preparations such as solutions, ointments, emulsions, suppositories, polymer-based drug forms, etc. whereby significantly longer useful lives are achieved.

Well-known technical solutions

Known technical solutions relate to the stabilization of the oxidation-sensitive active ingredient with the aid of a stabilizer which directly or indirectly interferes with a mechanism of oxidative degradation or with the aid of combinations of a stabilizer with synergists, which usually themselves have no stabilizing properties, but the stabilizer in This will give stabilizing effects over a certain period of time, which in many cases will not suffice for industrial production, especially when it comes to solutions. It is also not prevented that the oxidation mechanism is continued by another way, which z, B, despite

20. expresses the stabilization measure by discoloration, or thereby when external or internal stability-influencing factors, such as light, oxygen, container, temperature,

220475

pH, buffering and the like, the desired stabilization effects no longer occur.

Discolored pharmaceutical preparations whose active ingredient content no longer meets the requirements or those for which the harmless use is no longer possible due to an excessive proportion of in particular toxic decomposition products must be discarded and cause economic losses.

The example of Epinephrinehydrogentartrats in eye drops for glaucoma treatment known technical solutions are explained in more detail. Known technical solutions for the stabilization of epinephrine in eye drops use stabilizers such as ascorbic acid, sodium pyrosulfite, 8-hydroxyquinoline.

35 sulfate, cysteine, N-acetylcysteine and erythorbic acid *

Other known technical solutions use combinations of one of the stabilizers mentioned with synergists, which include citric acid, tartaric acid and phosphoric acid. These approaches show availability periods between 1 and 5 months at room temperature. It must be emphasized that the determination of the active substance content may not be made by measuring the discoloration and not with the help of a determination method, which detects occurring decomposition products, otherwise higher levels of active substance are simulated. These approaches have the disadvantage that discoloration occurs irregularly, especially in brown glass containers during the period of usefulness. Thus, none of the known technical solutions for epinephrine eye drops offers good conditions for industrial production.

Object of the invention

The invention is based on the object, which is present in known technical solutions for stabilization deficiency, such as influencing only one direction of the oxidative decomposition mechanism, irregular discoloration, low stability under conditions to which the drug may be exposed during manufacture, transportation, storage and use, and to allow their production under industrial conditions by extending insufficient

-3- 220475

Essence of the invention

According to the invention, the problem of stabilizing oxidation-sensitive drugs or excipients by the method of combining at least three pharmaceutical excipients, which is based on the fact that the combination shows a superadditive stabilizing effect by the manner described below. Each of the individual components influences a different direction of the oxidative decomposition mechanism. The combination consists of a discoloration protector (eg sodium pyrosulfite), an antioxidant (eg N-acetylcysteine) and a complexing agent - diethylenetriaminepentaacetic acid (DTPA), whose mode of action is characterized by the fact that each aer single component is only slightly effective that dual combinations of these components at most additive or show synergistic effect enhancement, and that only the triple combination produces a superadditive stabilizing effect,

The method further includes the dependence of the potency of the superadditive stabilizing effect, based on the percentage decrease of the drug to be stabilized, on the concentration of the individual components which must be determined for each drug to be stabilized, concentrations above or below the optimal concentration for stabilization may be ineffective or even pro-oxidative. For the application example epinephrine eye drops this object is achieved according to the invention. The individual components or the entirety of the invention

85 solution have the following feature:

Sodium pyrosulfite itself is not a stabilizer but a discoloration protector. It prevents the early appearance of discoloration, which, owing to oxidation and further reactions, occurs even in very low concentrations of colored decomposition products. The drug loss itself is not affected. In combination with N-acetyl cysteine or with DTPA, it acts as a synergist,

N-acetyl cysteine acts preferentially as an antioxidant. It is also able to complex to a lesser extent. "In the presence of sodium pyrosulfite, interactions occur in such a way that

enhances the antioxidant effect of N-acetyl cysteine and prolongs the discoloration-inhibiting effect of sodium pyrosulfite

 Diethylenetriarnine pentaacetic acid (DTPA) is a chelating agent

) 0 Agent »It indirectly interferes with the decomposition mechanism by complexing metal ions that act as oxidation catalysts« In the presence of sodium pyrosulfite, its action is synergistically enhanced. Other known chelating agents, e.g. EDTA, are significantly less or not effective.

) 5 By the method of combining sodium pyrosulfite,

N-acetyl cysteine and DTPA, the described effect of the individual components is over-additive amplified, whereby so stabilized pharmaceutical preparations with oxidation-sensitive drug or auxiliaries over-additive longer than in the stabilization

LO with the help of only one or two components of the combination according to the invention can be used. A further effect of the method according to the invention is that the stabilized preparation is resistant to stability-influencing factors such as light, air, oxygen, oxidation catalysts,

L5 type of container, storage temperature, pH etc. significantly less sensitive. In addition, the method according to the invention has the effect that no discoloration occurs within the usable usability time and beyond.

embodiment

The inventive method will be explained below using the example of epinephrine eye drops for glaucoma treatment.

Composition of the Epinephrine Eye Drops According to the Invention: Variant I

1. Sodium tetraborate 0.90 g

2, diethylenetriaminepentaacetic acid 0.01 g 15 3. boric acid 0.40 g

4. Sodium pyrosulfite 0.30 g

5. N-acetylcysteine 0.10 g

6. Phenylethanol 0.50 g

7. Epinephrine hydrogen tartrate 1.00 g 50 8. Water ad 100.0 g

pH: 5.5-6.5

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Variant II

1. Diethylenetriamine pentaacetic acid O ₁ Ol g

2 * sodium pyrosulfite 0.30 g

3. N-Azetyicysteine 0.10 g

135 4, sodium chloride 0.60 g

5. phenylethanol 0.50 g

6 "epinephrine hydrogen tartrate 1.00 g

7. Sodium hydroxide solution (40 g / l) ad pH 5.5-6.5

8. Water ad 100.0 g

The decision on the preferred use of the buffered (I) or unbuffered (II) variant requires a clinical trial »The stated stabilizer concentrations are optimal, which has been determined in detail" Phenylethanol serves as a preservative "

Production: Variant Σ:

The solution of the components in a proportionate amount of water

is carried out in the order 1. - 8., whereby it should be noted that DTPA dissolves only in an alkaline environment. Epinephrine hydrogen tartrate is added to the already stabilized, ionized and preserved solution and then made up to 100.0 g with water. The finished solution is filtered bacteria-free and filled under aseptic conditions and optionally under inert fumigation in sterilized vessels,

Variant ΙΪ:

The solution of animal components takes place in the order 1 - 9, wherein it should be noted that first DTPA is dissolved in a small amount of sodium hydroxide solution. After all other ingredients have been dissolved and the total amount is about 85-9Og, is adjusted with sodium hydroxide solution to the specified pH and then filled with water. The further treatment is carried out as in variant I.

Proof of the superadditive effect:

For the quantitative determination of the superadditive stabilizing effect with the aid of the stabilization method according to the invention, load tests were carried out at elevated storage temperature (40 ^° C.). They illustrate the improvement of

Stabilizing effect in %, d, h. the difference in the active ingredient content of epinephrine solutions with and without stabilizing additives and the percent reduction in the decomposition rate, by stabilizing additives, compared to the pure pH epinephrine solution (Table 1).

To demonstrate the effects of the solution according to the invention on the useful life of epinephrine eye drops results of o, g. Prescriptions depending on container and fumigation in the long-term test, at room temperature (25 ⁰ C) shown, with a comparison with a selection of known technical, nischer solutions is made (Table 2).

Table 1: Quantitative determination of the stabilizing effect of 1% epinephrine hydrogen tartrate solutions with stabilizing additives at 40 ° C

    additive Improvement of the stabilizing effect in % 2 6 8 12 20 days 0 0 0 1 Through cut Reduction rate 2 6 8 12 0 0 0 the Zer- in % 20 days ι I'II cut through Discoloration 2 6 8 12 20 Assessment of the stabilizing effect additive effect enhancement I sodium pyrosulfite 0 4 3 2 2 0 0 19 13 8th 0 0 l • no stabilizer, but discoloration protector \ over- additive ~ \ gain-boost II N-acetylcysteine 4 2 2 1 12 2.8 33 9 8th 4 3 15.2 ο * ♦ ♦ ¹ + antioxidant DTPA 2 13 14 10 12 1.6 17 61 61 41 7 9 ₊ ♦ ₊ ♦ • f Complex artist I + II I j 9 13 13 9 4 11.6 75 62 43 38 38 55.2 - - - C) Increasing the impact of synergies I + III 7 6 5 3 22 10.8 58 29 22 12 38 47.8 - - + + 1 Effectiveness I Strengthening I through synergism II + III 1 ⁶ 19 20 20 4.8 50 90 87 83 12 25 C) * * ♦ I I + II + III t I 19 99 i 69 i 85.6 i _

- no discoloration (+) isolated discoloration + discoloration

• YF

22 04 7 5

Table 2: useful life of the solution according to the invention in comparison with known technical solutions

-O

at 25 C storage temperature

! stabilizing

with

Useful life (months) Discoloration

Au Au 'PEND N _o -gas in ί

* Au}

according to the invention

18 24

! pyrosulfite

1.5 2.5 2.5

isolated, irregular

iNatriumpyrosulfit + l

8-hydroxyquinoline-j sulfate j

isolated, irregular

ascorbic acid

Au standard eye drops bottles made of brown glass Au '' brown glass eye drop bottles of improved glass quality PEND containers made of low-density polyethylene

Claims (8)

Invention claim 220475 1, method for stabilizing pharmaceutical preparations containing oxidation-sensitive ingredients, characterized in that a superadditive Stabilisierungseffeiet is achieved by means of the combination of at least three pharmaceutical Kilfsstoffen, whereby, first, the usability times uer pharmaceutical preparations substantially lengthened and second colored by preventing the occurrence of decomposition products which Utility properties are improved. 2, The method of item 1, characterized in that it is drugs or excipients is in the oxidation-sensitive constituents, the main degradation mechanism is an oxidation, at the same time can subsequently proceed other chemical _reactions} before or, such as in epinephrine, physostigmine or aminophenazone # 3 The method of item 1, characterized in that it is in the three adjuvants for stabilizing a coloring protector, an antioxidant and a chelating agent, which, in itself, affect different causes OCE decomposition. 4. The method according to item 1 and 3, characterized in that it is the discoloration preferably sodium pyrosulfite, wherein the antioxidant is preferably N-acetyl cysteine and the complexing agent to Diethylentriaminpentaessigsäure (DTPA). 5, process according to point I ₁ 3 and 4, characterized in that the superadditive stabilizing effect is achieved by the combination of said auxiliaries, each individual component is only slightly effective and support the respective specific activity property by mutual stabilization or - · 10 - 6. Method according to items 1, 2, 3, 4 and 5, characterized in that the optimum concentrations of said excipients (eg, sodium pyrosulfite, N-acetyl cysteine and DTPA) are suitably separated and specific for each pharmaceutical preparation must be determined depending on the drug concentration, 7. The method according to item 1, 2, 3, 4, 5, and 6, characterized in that, for example, epinephrine eye drops can be stabilized for glaucoma treatment, 8. The method according to item 1, 6 and 7, characterized in that the concentrations of 0.3 % sodium pyrosulfite, 0.1 % N-acetyl cysteine and 0.01 % DTPA are optimal for 1% epinephrine hydrogen tartrate eye drops,
9, method according to item 1 and 7, characterized in that the production of the stabilized epinephrine eye drops after öer in the embodiment set order.