ff0111.fm Page 38 Wednesday, June 22, 2011 2:45 PM

Original investigations

COMPARATIVE PHARMOCHEMICAL ANALYSIS OF LONG-ACTING GENERICS (DEPOT) OF OCTREOTIDE

Yu.B Belousov.¹, A.V.Kamaev, S.K.Zyryanov ², Yu.B. Zverkov, A.A.Lelichentsev

OOO (Limited Liability Company) "NAKFF", Moscow,

The State Educational Institution of Higher Professional Education "The Russian State Medical University named after N.I. Pirogov of the Federal Agency for Health Care and Social Development”

A pharmochemical analysis was conducted to evaluate the equivalence of long-acting generics of octreotide and original drug. According to its results the basic pharmochemical properties of generics are different from those of the original octreotide, it may cause changes in efficacy and safety of generic drugs versus original product.

Key words: pharmochemical analysis, long-acting forms of octreotide, original drug and generics.

Evaluation of comparability of efficacy and safety of original and generic drugs was always of great interest. The use of generic drugs in medical practice will allow to use limited budgetary resources more efficiently and to provide modern medical care to a larger number of patients, but this economic effect will be achieved only on condition that we prove equivalence of the compared drugs.

However, it is quite a difficult task to determine equivalence of the drugs, since the notion of "equivalence" in this case includes not only proof of identity and equality of the active substance in the preparations studied (i.e., proof of pharmaceutical equivalence), but confirmation of the similarity of pharmacokinetic parameters (i.e., confirmation of bioequivalence), as well as proof of therapeutic equivalence of the compared drugs. [1]

It is only through determination of the equivalence of all the studied parameters that original and generic drugs can be considered interchangeable.

The confirmation of equivalence of preparations with modified release is of particular difficulty.

Medications in the forms with modified release are a group of formulations with special release mechanism and character of drug release. Confirmation of equal content of active substance in the generic and original preparation is not yet indicative of their interaction substitutability, since the main purpose of dosage forms created with a modified release is to maintain stable concentrations of drug in the patient's body for a long time.

______________________________________________________________________________

¹ Belousov Yuri Borisovich, corresponding member of RAMS, professor, head of the Department of clinical pharmacology of RSMU named after N.I.. Pirogov, e-mail: belouspharma@mtu-net.ru.

² Zyryanov Sergei Kensarinovich, professor at the Department of clinical pharmacology of RSMU named after N.I.. Pirogov, e-mail: serguei_kensarin@hotbox.ru.

Medications in the form of depot (from the French: depot - accumulation point, Lat. depono - hold over; synonym: pharmaceutical depot forms) are long-acting parenteral dosage forms for injections and implantations into the body ensuring the formation of the depot of the drug and its subsequent slow release. Medications in the form of depot are always released into the same environment in which they are accumulated, in contrast with the changing environment of the gastrointestinal tract. They can be administered at longer time intervals (from several weeks to several months) in comparison with oral long-acting dosage forms. In the depot formulations absorption is usually achieved by using poorly soluble compounds of the active substances (salts, esters, complexes), of their chemical modification (e.g., microcrystallization), with insertion of the drugs in a viscous medium (oil, wax, gelatin or a synthetic medium), and using systems of delivery (microspheres, microcapsules, liposomes). At the same time mechanisms of the slowing are also different: for example, slow release of drug from the oily suspensions may be the result of slow decomposition (hydrolysis of the ester or complex) or the slow dissolution of poorly soluble compounds. The current nomenclature of depot formulations includes: 1) injectable preparations: oil solution, depot suspension, oil suspension, microcrystalline suspension, micronized oil suspension, suspensions of the insulins, injectable microcapsules, microsphere injection, 2) implantation forms: depot tablets, subcutaneous tablets, subcutaneous capsules (depot capsules), intraocular films, ophthalmic therapeutic systems and intrauterine systems [2].

The properties of the depot formulations in the treatment of diseases with a chronic, life-long course are of particular importance, since a stable concentration of drug substance in the body is a certain guarantee of adequate controls over the course of the disease and stable (compensated) of the patient, in which the risks of complications and relapses are significantly reduced.

An example of such chronic diseases which often requires life-long treatment is acromegaly - a serious neuroendocrine disease caused by chronic hyper-production of growth hormone (somatotropin, GH) in patients with a completed physiological growth. Lack of timely and adequate treatment of acromegaly leads to disability and increased mortality due to severe complications, the main of which is the damage of cardiovascular system. That is why all the patients with verified diagnosis, except in very rare cases where there is a comorbidity with an unfavorable life prognosis, should be treated [3-5].

About 30 years ago a hypothalamic factor was discovered, which later would be called somatostatin - a cyclic peptide which consists of 14 amino-acids and inhibits the secretion of the growth hormone. In addition to suppressing secretion of the growth hormone, somatostatin inhibits many physiological functions in other organs via autocrine and/or paracrine regulation. Somatostatin acts through specific membrane receptors. Presence of somatostatin receptors has been demonstrated in many organs, particularly in various areas of the brain, adenohypophysis, pancreas, mucous membrane of the gastrointestinal tract, organs of the immune system. An ability of somatostatin to inhibit functional activity of various organs has served as an impetus to its use as a therapeutic agent in some diseases. In human patients, in the majority of tumors formed from the cells of target organs for somatostatin, somatostatin receptors have been revealed with a high density. Five subtypes of somatostatin receptors have been identified. In the majority of STH-producing pituitary adenomas subtypes 2 and 5 are expressed (92%), while subtypes 3 and 1 are expressed in approximately 45% of cases, significantly less common subtype 1 is met [6].

Practical use of natural somatostatin for therapeutic purposes is impossible, because of its very short half-life (less than 3 minutes), as well as post-infusion hyper-secretion of hormones (rebound effect).

Due to the success of pharmacology, long-acting selective analogs of natural somatostatin have been created – octreotide and lanreotide, which was a real revolution in the treatment of acromegaly [7]. Octreotide (which has been registered in the Russian Federation under the tradename sandostatin) is the first analogue of somatostatin, used in clinical practice since the mid-1980s, has a high affinity to somatostatin receptors of subtype 2, and its growth hormone-inhibiting activity is 45 times more active than the native hormone. At a daily dose of 100-500 mcg three times daily subcutaneously, octreotide significantly reduces the secretion of this hormone in 85%patients, while it induces normalization of the level of the growth hormone (somatotropin) and insulin-like growth factor-1 in 50 patients and 40%, respectively. It was shown that in these doses the drug is more effective with continuous infusion rather than with a rapid injection.

This fact, as well as inconvenience of administration three times a day, has contributed to the development of long-acting drugs. A long-acting form of octreotide for intramuscular injection was created, registered under the tradename Sandostatin LAR (Novartis Pharma AG, Switzerland). The implementation of the active ingredient in special microspheres of poly (dl-lactide-co-glycolide)-glucose polymer has determined its pharmacokinetic features, so that the number of injections was reduced to 1 per 28 days (10-30 mg i.m.), the effectiveness of treatment in this cases has increased, especially in cases of severe acromegaly in the background of a significant increase in indicators of growth hormone and IGF-1 [7].

Sandostatin LAR provides a stable and effective reducing of the levels of growth hormone and IGF-1 and successfully controls the symptoms of acromegaly, which has repeatedly been reflected in the publications of both foreign and domestic researchers. According to meta-analysis including results of 12 studies involving 612 patients with acromegaly, in comparison with treatment with Sandostatin LAR at doses of 20-40 mg normalization of GH and IGF-1 was achieved in 57 and 67%, respectively. In this case there was a significant improvement in systemic condition, of the cardiovascular system, of joints, reduction of intensity and frequency of headaches, of swelling of soft tissues. In addition, there was a significant reduction in tumor size in more than half of the patients, who received drug therapy [8, 9]. Similar results were obtained by national clinicians [10, 11].

The total experience for the drug of more than 600 patient-years has been accumulated in the world. Data on the clinical efficacy of generic drugs is extremely small – there has been one study involving 30 patients treated with Octreotide-Depo [12], and no study on the clinical efficacy of Octreotide-Long. Therefore, questions about the equivalence of different long-acting formulations of octreotide are highly relevant. The aim of this work was a comparative pharmochemical analysis of depot formulations of octreotide: of the drug Octreotide-Depo (JSC [closed joint stock company] "Farm-Synthesis", Russia), and Octreotide-Long (JSC [closed joint stock company] "F-Synthesis", Russia) - to examine the equivalence of this generics to the original drug.

Materials and methods

All the studies were performed in the testing laboratory of LLC (Limited Liability Company) "National Agency for Clinical Pharmacology and Pharmacy".*

Pharmochemical study was conducted on the following criteria: identification, assay, impurities, dissolution kinetics, suspendability, particle size, determination of heavy metals.

______________________________________________________________________________

* The studies have been conducted under the sponsorship of Novartis company.

The samples of drugs had been purchased at retail from a distributor, drugs of the following series were studied:

- Octreotide-Depo: batch 01062010, expiry date: 06.2013, batch 02042010, expiry date: 04.2013, batch 01062010, expiry date: 06.2013.

- Octreotide-Long: batch 04042010, expiry date: 04.2012, batch 06,082,010, expiry date: 08.2012, batch 04042010, expiry date: 04.2012.

Identification of the samples of octreotide received for analysis from different manufacturers was confirmed by high performance liquid chromatography (HPLC) by comparing the retention time of octreotide in the chromatograms of standard and test solutions.

Assay was performed by HPLC according to an external standard, including only freshly prepared solutions.

Determination of impurities is to compare the peaks in the chromatograms of solutions of the test solutions with the peaks in the chromatograms of standard sample and solution of a corresponding solvent by HPLC.

As far as convincing evidence base has been accumulated for the high efficacy and safety of the original depot form of octreotide (Sandostatin LAR), in pharmochemical studies we have carried out to assess properties of the generic depot formulations of octreotide using regulatory documents (RD), which regulate quality of the original drug (RD 42-11386-06).

 Table 1

Results of a quantitative assay of the level of octreotide in the formulations of Octreotide-Depo and Octreotide-Long

Results and discussion

The retention time of octreotide stock solution was 5.59 min, of octreotide test solution obtained from the drug Octreotide-Depo - 5.52 min, and the preparation of Octreotide-Long - 5.59 min.

Percentage of values of standard retention time and test samples was as follows: for Octreotide-Depo - 98.8%, for Octreotide-Long - 100%. All the values stay within an interval of allowed values from 98 to 102%.

In table 1 are represented data of the assay of the studied drugs – Octreotide-Depo and Octreotide-Long and requirements of regulatory documents.

As is shown in table 1, content of octreotide in the studied drugs while staying in the area of the lower allowable value of the interval meets the requirements of RD 42-11386-06.

The results of the assay of impurities are given in table 2.

From the Table 2 can be seen that the total content of the impurity in the preparations Octreotide-Depo and Octreotide-Long meets specified requirements, as well as RD 42-11386-06 and RD of Russian manufacturers. However, if we evaluate the content of individual impurities in accordance with the requirements of documentation for original drug, content of two individual unidentified impuities in the Octreotide-Depo falls outside the margin, while in the Octreotide-Long content of one individual unidentified impurity in the Octreotide-Depo falls outside the margin margin. Moreover, according to the norms and RD manufacturers (JSC [closed joint stock company] "Farm-Synthesis", Russia), and JSC [closed joint stock company] "F-Synthesis", Russia), the contents of a single unidentified impurity in each preparation exceed an acceptance limit, though not much.

Of great interest is the study of kinetics of dissolution, since evaluation of this parameter allows presumably estimation of release rate of the drug from the microspheres in the human body. Investigation of the kinetics of dissolution was performed on the instrument for assessment of dissolution dynamics for two values of pH (4.0 and 10.0).

Samples were taken at 1, 4 and 24 hours. Assay of dissolved octreotide was determined by HPLC. Preparation of solutions, their dilution, as well as calculation of the content of octreotide, which be merged into solution from the declared amount, were carried out strictly according to RD for the original drug.

Table 2

The results of determination of impurities in the pharmaceutical drugs Octreotide-Depo and Octreotide-Long

The results of dissolution test are presented in the tables 3-6.

Table 3 and 4 shows, that at each control point a drug Octreotide-Depo has a higher percentage of dissolution than it is regulated by the RD of the original drug. Consequently, the ability to create a depot active substance in the body of patient is less pronounced for the investigational product than for the original drug.

Table 5 and 6 shows, that at each control point the drug Octreotide-Long also has a higher percentage of dissolution, thus not staying within RD 42-11386-06, requirements applicable to the original product. Consequently, in respect of the drug Octreotide-Long the following conclusion is also relevant: the ability to create a depot of the active substance in the body of patient for the investigational product is expressed to a lesser extent than that of the drug Sandostatin LAR.

In evaluating the studied drugs in parameters "Suspendability" and "Particle Size" significant deviations from parameters of RD original product were not found.

To determine assay of heavy metals in pharmaceutical drugs presented for the study was used physic-chemical method of analysis: mass spectrometry with inductively coupled plasma.

Table 3

Results of the test of dissolution of six study samples of the drug Octreotide-Depo, pH 4.0

Time, h	Amount of dissolved octreotide (%)
	Sample 1	Sample 2	Sample 3	Sample 4	Sample 5	Sample 6	RD
1	5.3	6.5	4.8	5.1	4.2	5.3	--> - 0 +    дата: 4 апреля 2014    Загружено переводчиком: Агафонычев Владимир Александрович Биржа переводов 01    Язык оригинала: русский    Источник: OOO (Limited Liability Company) "NAKFF", Moscow, The State Educational Institution of Higher Professional Education "The Russian State Medical University named after N.I. Pirogov of the Federal Agenc Главная Категории Переводчики Пользовательское соглашение О проекте Вход для переводчиков Тех. поддержка: support@mirznaet.ru