Endocrine system is a collection of several glands which secrete different types of hormones into the blood stream. The 'Pituitary gland' is considered as the master gland of this system as it regulates the secretion of hormones by some other glands [1].
Diabetes
Diabetes is a metabolic disorder - Most of the food we eat is divided into a form of sugar called glucose which is a source of energy for the body. A hormone called "Insulin" secreted by pancreas, an organ which lies beyond the stomach helps in moving down glucose into the body cells where it gets converted into energy [2].
In some cases, the body becomes incapable of producing required amounts of insulin or unable to use its own insulin as proper as it should. This results in high amounts of glucose in the blood and therefore it passes out of the body through urine. This condition is known as Diabetes [3].
Diabetes Mellitus [4, 5]
It is a systemic metabolic disorder which is characterized by chronic hyperglycemia due to secretion of low amounts of insulin, pripheral resistance to insulin action or both.
It is mainly classified into four types:
Type I generally occurs in non-obese young people which is either autoimmune mediated or idiopathic destruction of beta cells of the pancreas which produce insulin. It is characterized by insulin defeciency in the body.
Type II which is characterized by peripheral resistance to the action of insulin and lack of insulin secretory response occurs in old age roup people who are generally obese.
Other types include Diabetes melitus caused due to genetic defects in the function of beta cells of pancreas, action of insulin or due to the diseases of exocrine pancreas. Insulin defeciency which is drug induced of chemically induced also cause Diabetes mellitus.
Gestational Diabetes mellitus is a condition where abnormal carbohydrate intolerance is reported which starts or is first recognized during pregnancy. The two most common contributors to this condition are impaired function of beta cells of pancreas and insulin resistance. It is generally noted in the second trimester of pregnancy [6].
Diabetes Insipidus [5, 7]
It is a chronic hypothalamic disease caused due to impairment in the production of a hormone known as 'Vasopressin' (Anti-diuretic hormone). In this condition, the individual's kidneys become incapable of retaining water. It is generally characterized by
Diabetes insipidus is classified into four forms: Neurogenic, Dipsogenic, Gestagenic and Nephrogenic. It is differentiated from Diabetes mellitus by high specific gravity of urine and glycosuria in Diabetes mellitus.
Diabetes Statistics
There are around 177 million people suffering with diabetes in the world according to WHO estimate for the year 2000. It predicts that, this number will go up to 300 million by the year 2025 which will be roughly around 9% of the world population.
According to IDF, there is an estimate of over 2 million diabetic patients in UK alone in which 750,000 people are undiagnosed [8].
According to a very recent report entitled as "Diabetes in the UK 2009" which provides important statistics on Diabetes, the middle-aged men are at a double risk of developing diabetes when compared with the women of the same age group. And also, during the last 12 years, the men between the age group of 35-44 are more prone to this disease by four times [9].
INSUMAN COMB (Biotecnological Product)
Insuman Comb is a suspension for injection in a cartridge. Each ml contains about 100 IU (International Unit) of human insulin. Generally each cartridge contains 2 ml of suspension for injection which is equivalent to 300 IU of insulin [10].
Physical properties: Insuman Comb is a biphasic isophane insulin suspension which contains about dissolved insulin and crystalline protamine solution.
Pharmaceutical Form: This is a suspension for injection in a cartridge.
Dose and Method of administration: Different types of doses and timings must be adjusted to different patients depending up on patients age, physical activity etc. The average insulin requirement is 0.5 to 1.0 IU per kg body weight per day. Insuman Comb 25 is injected subcutaneously 30-45 minutes before a meal. Adjustment in the dosage is necessary when a particular patient is transferred from one treatment to the other i.e. from animal insulin to human insulin, from one human insulin preparation to the other etc [11]. Close metabolic monitoring is required during transferring the treatment. Improved metabolic control may result in insulin sensitivity which leads to reduced insulin requirement.
Administration:
Insuman comb 25 is administrated subcutaneously. This drug has been developed for use in Optipen series. Due to insulin absorption and blood glucose lowering effect the injection area must be rotated from one injection to the other.
Contraindications:
This must not be administrated to the patients who develop hypersensitivity reactions to active drug substance or either excipients. This drug must not be administrated intravenously.
Precautions for use:
Patients who develop hypersensitivity reactions to this drug and can't use other drugs may also be administered, but under medical supervision.
Some patients may be allergenic to animal insulin; those patients must undergo intradermal skin testing prior to the treatment.
Some patients mainly elderly people suffer from renal impairment where insulin requirements fall down. So, special care must be taken for these patients.
Drug Interactions:
Substances that increase susceptibility to hypoglycaemia [12] include oral antidiabetic agents, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.
Substances that reduce the blood-glucose-lowering effect include corticosteroids, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens , phenothiazine derivatives, somatropin, sympathomimetic agents (e.g. epinephrine, salbutamol, terbutaline), thyroid hormones, protease inhibitors and atypical antipsychotic medicinal products (e.g. olanzapine and clozapine).
Other drugs like Beta blockers, lithium salts or alcohol may enhance or weaken the blood glucose lowering effect of insulin.
Pregnancy and Lactation:
Insulin does not cross the placental barrier so that there may not be a big problem for pregnant ladies. But for the pre existing or gestational diabetes medical supervision is essential because insulin requirements may get reduced in first trimester and the condition gets worse by second and third trimester.
No effect is seen on suckling child so it can be given to lactating women but slight change in diet should be done.
Undesirable side effects [13]:
Hypoglycaemia is the most general and common side effect in insulin therapy, this is due to only one reason i.e. dosage which is constant and varies from one individual to the other. If this effect increases, then it leads to neurological damage. Some other adverse effects are:
Immune system disorders: Immediate type allergic reactions (hypotension, angioneurotic oedema, bronchospasm, generalised skin reactions), anti-insulin antibodies. These reactions may be due to active ingredient or excipients.
Metabolism and nutrition disorders: oedema and sodium retention are common metabolism disorders and these generally occurs if intensified insulin therapy is given to a poor metabolic disorder.
Eye disorders: One of the major eye disorders is the visual impairment which occurs due to temporary alteration in the turgidity and refractive index of the lens. Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.
Skin and Subcutaneous tissue disorders: Lipodystrophy (degenerative condition of body adipose tissue) may occur at the injection site and this can be minimised by rotating the injection site frequently.
Overdose: Insulin overdose may to life threatening hypoglycaemia. In the starting stage it can be treated by giving oral carbohydrates or adjusting the meal patterns or by physical activities. In the severe cases it can be treated by giving intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
Mode Of Action:
Insulin
List of Excipients:
Protamine sulphate, metacresol, phenol, zinc chloride, sodium dihydrogen phosphate dehydrate, glycerol, sodium hydroxide, hydrochloric acid and water for injection.
Manufacture: Insuman Comb is recombinant human insulin identical to natural molecule. It is produced by recombinant DNA technology in a modified E.coli strain as a fusion protein with a bacterial peptide attached [14]. The protein is processed after production to remove the bacterial component, rendering it identical to the human molecule. Then the product is purified by using chromatographic techniques. Later this product is combined with all the excipients to form the final product.
Control on starting materials:
Active ingredient:
Active ingredient specifications comply with the Ph. Eur. and USP. Additional tests are carried out according to the methods developed by the company. All tests are validated.
Development genetics
The genetic information cloned into the vector used for the production of Insulin HGT has been described in its key elements. Three different plasmids were used as source material for the construction of the expression vector. The nucleotide sequence of the coding region of the fusion protein, the promoter and the junctions between the individual plasmids were confirmed by DNA sequencing. A complete DNA sequence has been provided.
Seed bank system
Sufficient details on the preparation and storage of the master cell bank (MCB) and working cell banks (WCB) are provided. All these seed banks were tested for identity, growth rate, viability, microbial contamination, plasmid retention.
Fermentation and harvesting
The fermentation process is performed in a closed system and then harvesting is done properly as per the guidelines given by the company.
Downstream modification and purification
The downstream processing of the fusion protein to human insulin is a sequence of modification and purification steps. Certain steps are specifically designed to remove specific contaminants. All the steps are well validated and sufficient in-process controls are performed.
Characterisation
Evidence of the structure of insulin was adequately provided by using several techniques (mass spectroscopy, protein sequencing and H-NMR).
Process validation and batch analysis
The full-scale process has been adequately validated and the data from production runs are provided. Batch analysis of batches produced on production scale and the batches used for the pre-clinical and clinical studies have been provided. The data demonstrate sufficiently the consistency of the production and the purification process.
Other ingredients
The excipients used are described in Ph.Eur., USP or USP/NF.
Shelf Life: Shelf life of this product is 2 years. Once the cartridge has opened it can be stored till 4 weeks below 250c away from direct sunlight. It should not be stored in refrigerator. Unopened containers must be stored at 20c - 40c but should not freeze.
Special precautions for disposal and other handling:
The cartridges are to be used in conjunction with an insulin pen such as OptiPen and other pens suitable for Insuman cartridges and as recommended in the information provided by the device manufacturer. And the instructions by the manufacturer should be followed perfectly.
Cartridges usage is utmost important one. Before insertion into the pen, Insuman Comb 25 must be kept at room temperature for 1 to 2 hours and then resuspended to check the contents. Each cartridge contains three small metal balls to facilitate quick and thorough mixing of the contents.
Later on, when the cartridge has been inserted into the pen, the insulin must be resuspended again prior to each injection. This is best done by gently tilting the pen back and forth (at least ten times).
A uniform suspension with milky apperance should be obtained after resuspension. If the suspension is found to be clear, or if clumps, particles or floccules appear in the catridge, then insuman comb 25 must not be used. These consequences yield a catridge with frosted appearance. When the insulin requirements changes, it is also very much essential to change to a new catridge as per the individual's need.
Before injection, air bubbles must be removed if any from the catridge and refilling the empty catridges is not recommended.
Insuman Comb should not be mixed with solutions containing thioles and sulphites as reducing agents.
Marketing authorisation and Regulatory issues relating Insuman [15]:
The European Agency for the Evaluation of Medicinal products (EMEA) has issued a warning about the leakage of Insuman Comb infusions. In a number of the rare cases reported, it appears that insulin leaked out from the top rim of the cartridge below the metal ring and the insufficient supply of insulin led to hyperglycaemia with hospitalization in four cases.
The following necessary precautions are recommended:
The MHRA has been informed by Sanofi-Aventis UK Ltd that damage can occur to an internal component of the Optipen Pro insulin pen injection system.
In devices where this damage has occurred, the dosage button may not lock when it is depressed fully following the injection of the desired dose of insulin. The button will not be retained in the end position and will return to the extended (start) point. This could lead patients to believe that the injection has not been successful and to consider performing another injection of insulin.
Patients using the Optipen Pro insulin pen injection system should be made aware of this potential problem and advised that prior to each injection, they should perform a safety test in accordance with the instructions for use to ensure that the device is functioning correctly. Those experiencing this problem with the pen should stop using the device and replace it with a new one. Alternative systems are available for the administration of Lantus™ and Insuman™ insulins. Patients who are uncertain of the dose administered should seek prompt medical advice.
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