RU2304769C2 - Method for testing the quality of medicinal preparations - Google Patents

Abstract

FIELD: medicine, clinical pharmacology, forensic medicine.

SUBSTANCE: in the course of testing the quality of solutions for injections they should be injected under the skin of a piglet's abdomen at the volume being sufficient to create "lemon peel" effect, then one should fix the time, detect the dynamics of post-injectional inflammation of skin and subcutaneous-fatty fiber and in case of irreversible character and the onset of necrotic alterations it is possible to conclude upon low safety of preparations under testing and the chance for provoking post-injectional necrosis due to their application. The innovation provides the chance to detect medicinal iatrogeny due to widening the information upon the quality of medicinal preparations in the form of either availability or absence of necrotic action.

EFFECT: higher quality of testing.

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Description

The invention relates to pharmacy, in particular to monitoring the effectiveness and safety of drugs, and can be used in the development of new drugs intended for injection, as well as in clinical, pharmacological and forensic medical evaluation of the quality of drugs of certain manufacturers and series.

There is a method of examining the effectiveness and safety of dosage forms for injections (solutions for injection) (Practical Guide to the registration of medicines. - M .: Information and publishing agency "Remedium", 2001. - P.73-76, 161-192) examination of compliance of their quality with the requirements of pharmacopoeial articles.

The disadvantage of this method is the limited ability to detect low quality drugs due to the lack of information on the quality of drugs in the form of their necrotic activity. With the injection of drugs into various tissues of our body under these conditions, the necrotic activity of drugs is not taken into account and is not evaluated. And it can be absent due to the presence of preserving activity or take place in the form of moderately or excessively pronounced necrotic activity, leading to non-specific necrotic damage to cells and tissues through their physicochemical denaturation. The fact is that in accordance with this method, each drug is produced with only one quality standard adopted for injection solutions, regardless of the list of tissues of our body into which injection of the drug is recommended or possible (out of ignorance, inexperience). At the same time, physicochemical, biochemical, biophysical, systemic and functional indicators of the qualitative state of various tissues are different. Especially their range is large in the presence of pathological processes, therefore, after the injection of the same drug with the same quality into them, different post-injection effects occur in different tissues, namely, some tissues can fully maintain their viability, since the changes in their condition that have arisen are insignificant, very short-term and quite reversible, some tissues are significantly inflamed, but the inflammation can also be reversible and conditionally safe, and some tissues may receive excessive "pharmaceutical" changes, leading to a partial or complete loss of viability. So, in accordance with the specified quality standards, many injectable solutions are acidic and have a pH below 5, and sometimes below 3, regardless of the volume of the solution in the dosage form for injection. Therefore, after the injection of small volumes into large volumes of liquid colloidal media (such as blood, synovial, peritoneal, pleural fluids), which have significant fluidity and buffering, these tissues can fully maintain their viability by maintaining their homeostasis due to intensive and effective processes diffusion and neutralization reactions in them. At the same time, after the injection of the same drugs into biological fluids in volumes comparable to or greater than their volume, as can happen when the end of the injection needle is placed in small confined spaces with a low content of liquid colloidal media (such as subneural , subfascial spaces, uninflamed skin, subcutaneous fat), these tissues and other biological objects located in them can completely lose their viability due to immediate fuss repentant and long-lasting significant "pharmaceutical" changes in their homeostasis due to the excessive prevalence and prolonged presence of the drug in the tissues.

The aim of the proposed solution is to expand the ability to detect drug iatrogenism by expanding information on the quality of drugs.

The essence of the invention lies in the fact that in the method for examining the quality of injectable solutions by analyzing the compliance of their quality with the requirements of the pharmacopoeial articles, the studied drug is additionally injected under the skin of the abdomen of the piglet in an amount sufficient to create the effect of a lemon peel, time is noted, the dynamics of post-injection inflammation is determined skin and subcutaneous fat and when it becomes irreversible and the occurrence of necrotic changes are judged on the low safety of Ratov and the possibility of provoking them Postinjection necrosis.

Injection of the studied drugs under the skin can effectively identify the potential necrotic activity of injectable drug solutions, since the skin and subcutaneous fat are mandatory tissues through which the injection needle with the drug passes in any case when injected into any tissue of our body, since these Tissues are the first to advance the injection needle deep into our body. Therefore, it is the skin with subcutaneous fat that is more often than other tissues exposed to drugs that pour out from the injection needle when injected into skeletal muscles, blood vessels, and body cavities. In addition, subcutaneous fat is more vulnerable to injections of drugs with potential necrotic activity than skeletal muscle, blood, or parenchymal organs, since it is a less blood-supplying tissue. In addition, the skin and subcutaneous adipose tissue are easily accessible for drug exposure and visualization of postinjection processes in the experiment, and subcutaneous administration of drugs and the study of the dynamics of postinjection inflammation of the skin and subcutaneous fat do not require the participation of specially trained personnel conducting the examination, and may be made without the use of special equipment.

The use of pigs as a biological object makes it possible to increase the accuracy of the conducted experimental examination of the quality of drugs due to the fact that the physiological and biochemical processes inherent in the pig organism are closest to the processes occurring in the primates and humans in particular. Therefore, the pharmacological effects of drugs detected in experiments on pigs are more identical to human ones than those found in experiments on other animals. In addition, the features of the morphofunctional state of the skin and subcutaneous fat of pigs are most identical to the skin and subcutaneous fat of a person, therefore, the use of pigs optimizes a qualitative, native experimental study of the probable necrotic activity of the preparations.

In this case, the skin and subcutaneous fat of piglets are more sensitive to pharmaceutical influences than similar tissues of adult individuals due to the laws of general pharmacology (age-related pharmacology). In addition, the injection of drugs into the piglet’s body allows you to simulate the conditions for the interaction of drugs with the child’s body, which also increases the accuracy of the examination, since the indications for injection of the produced solutions do not have age restrictions and drugs can be introduced into the body of an adult or into the body a child who is more sensitive to drugs.

Injection administration of the test drug in a volume sufficient to create the lemon peel effect standardizes the examination and allows to maximize the degree of safety of the preparations, since the degree of their local physicochemical effect on the tissue is directly proportional to the volume of the injected solution.

The determination of the time of injection of the drug and the dynamics of post-injection inflammation of the skin and subcutaneous fat in the near future provides the accuracy of the examination and allows you to assess the presence or absence of necrotic activity of the drug, and also distinguish necrotic effect from allergic effects that may occur due to the presence of histamine-like substances in the drug. In this case, the occurrence of a necrotic effect a few minutes after injection of the drug allows us to conclude that there is an excessively pronounced denaturing pharmaceutical effect, and the traceless disappearance of post-injection infiltrate a few minutes after the injection of the drug allows us to judge the absence of necrotic activity and the high safety of the drug.

Examples.

1. Patient K., 29 years old, admitted to the neurological department in connection with an exacerbation of ankylosing spondylitis and chronic right-sided pneumonia, was prescribed intramuscular injections of 3 ml of a solution of 2.5% orthophene (75 mg) once a day and 2.5 ml of an aqueous solution of 10% cefazolin sodium salt (250 mg) 3 times a day. On the fourth day after the start of the course treatment with these drugs, a tight, painful infiltrate formed in the depths of the left gluteal region, which then transformed into a post-injection abscess after 2 days.

During the forensic and clinical-pharmacological examination of the causes of post-injection necrosis, it was found that the following drugs were used in the treatment of the patient: cefazolin-acos 1.0 g (Synthesis OJSC, Kurgan, series No. 291004), orthophene solution 2.5 % for injection in ampoules of 3 ml (OJSC "Biochemist", Saransk, series No. 80405). The analysis of normative and technical documents characterizing their quality showed that the quality of the drugs used in the clinic fully complies with the requirements of pharmacopeia articles. However, with an additional experimental examination of the quality of these preparations of the indicated manufacturers and series carried out on 2-month-old pigs, it was found that after injection under the skin of the abdomen with an aqueous solution of 10% cefazolin-akos and a solution of 2.5% orthophene in a volume sufficient to creating a “lemon peel”, fixing the time of injection and determining the dynamics of post-injection inflammation of the skin and subcutaneous fat, post-injection inflammation of the skin and subcutaneous fat had different equality. After the injection of the cefazolin-acos solution, the inflammation was reversible and disappeared without a trace after 27 minutes, and after the injection of the orthophene solution, the resulting post-injection inflammation of the skin and subcutaneous fat acquired an irreversible character, resulting in necrosis and the formation of an abscess. In this regard, a conclusion was made about the high safety of cefazolin-acos and the low safety of a solution of 2.5% orthophene due to the presence of necrotic activity in this drug and the possibility of provoking it with post-injection necrosis. An analysis of the composition of orthophene revealed the presence in it of 20% propylene glycol and 4% benzyl alcohol, i.e. 24% alcohols, which could be the reason for the necrotic effect of the drug.

2. Patient P., 27 years old, who was admitted to the surgical department of the CRH with a diagnosis of exacerbation of chronic osteomyelitis of the right tibia, was given intravenous injections of a solution of lincomycin hydrochloride 30% from 1 ml ampoules after dilution in 250 ml of a 0.9% sodium solution chloride 2 times a day. After the second injection of the antibiotic, an allergic complication occurred in the form of angioedema. Lincomycin hydrochloride injections were discontinued and an intravenous injection of 10 ml of 10% calcium chloride was prescribed. During the first injection of a solution of calcium chloride into the ulnar vein, the patient felt a burning pain in the elbow, after 7 minutes an area of bright red hyperemia with clear boundaries appeared, which then acquired a purple-bluish color after a few minutes, and after 5 minutes days abscessed despite ongoing chemotherapy with gentamicin.

During the forensic and clinical-pharmacological examination of the causes of post-injection necrosis, it was found that the following drugs were used in the treatment of the patient: lincomycin hydrochloride solution 30% 1 ml in ampoules (Dalkhimfarm OJSC, Khabarovsk, series No. 260704), calcium chloride solution 10% for injection in ampoules of 10 ml each (FSUE Moskhimfarpreparat named after N.A. Semashko, Moscow, series No. 60105) and a solution of sodium chloride 0.9% isotonic 250 ml for infusion (ZAO Rester, Izhevsk, series No. 981004). The analysis of normative and technical documents characterizing the quality of the drugs of these manufacturers and series showed that the quality of the drugs used in the clinic fully complies with the requirements of pharmacopoeial articles. However, with an additional experimental examination of the quality of these preparations of the indicated manufacturers and batches carried out on 2-month-old piglets, it was found that after injection under the skin of the abdomen of an aqueous solution of lincomycin hydrochloride 30% 1 ml diluted in 250 ml of a solution of 0.9% sodium hydrochloride and a solution of 10% calcium chloride in volumes sufficient to create a lemon peel, fix the time of injection and determine the dynamics of post-injection inflammation of the skin and subcutaneous fat, postin Injection inflammation of the skin and subcutaneous fat had a different orientation. After injection of a solution of lincomycin hydrochloride and sodium hydrochloride, the inflammation was reversible and disappeared without a trace after 20 minutes, and after injection of a solution of calcium chloride, the skin in the area of post-injection infiltrate reddened after 6 minutes, then after a few minutes acquired a purple-bluish color with clear boundaries, and then after 3 days there was an abscess of this area of the skin and subcutaneous fat. In this regard, the conclusion was made about the high safety of lincomycin hydrochloride and sodium chloride preparations, as well as the fact that the quality of 10% calcium chloride solution in 10 ml ampoules (series No. 60105) produced by FSUE Moskhimpharmpreparaty im. N.A.Semashko meets the requirements of the relevant pharmacopoeial article, but despite this, this drug has low safety due to the presence of necrotic activity and the possibility of post-injection necrosis provoked by it. A histological analysis of sections of the skin and subcutaneous fat from the area of post-injection inflammation in experimental animals confirmed the development of calcium necrosis of the cellular and subcellular structures of these tissues.

Thus, the proposed method expands the possibilities for identifying drug iatrogeny by expanding information on the quality of drugs in the form of the presence or absence of necrotic effect.

Claims (1)

A method for examining the quality of drugs, including analyzing the quality of injection solutions according to the requirements of pharmacopeia articles, characterized in that they are additionally injected under the skin of the pig’s abdomen in an amount sufficient to create the effect of a “lemon peel”, time is noted, the dynamics of post-injection skin inflammation and subcutaneous are determined -fat fiber and when it becomes irreversible and the occurrence of necrotic changes, they judge the low safety of drugs and the possibility of provoking them and post-injection necrosis.