INTRODUCTION:

According to WHO definition, new fixed-ratio combination products are regarded as new drugs in their own right and they are acceptable only when (a) the dosage of each ingredient meets the requirements of a defined population group, and (b) the combination has a proven advantage over single compounds administered separately in terms of therapeutic effect, safety or compliance. They should not be treated as generic versions of single-component products [1]. Combination therapy is commonly used in treatment of almost every area of diseases, especially hypertension, tuberculosis, malaria, diabetes and pain management, etc. Ideally, combination products can provide a synergistic effect of individual drugs with reduced side effects. From a compliance point of view, combination products provide a single pill, reducing the number of pills taken on a daily basis and therefore enhancing patient compliance.

Reducing the number of pills diminishes the complexity of the regimen, so that improved patient adherence is expected with combination products. To combine drugs belonging to different classes and having mechanisms of action that is complementary to each other, for example antihypertensive drugs, Telmisartan and hydrochlorothiazide. Using FDC products in tuberculosis and malaria control simplifies the doctor's prescription and patient's drug intake, helps patients adhere to treatment, precludes inadvertent monotherapy by the patient and therefore prevents the emergence of drug resistance due to missed dose of a constituent drug for example, Isoniazide and Rifampicin. Several fixed-dosed FDC products are commercially available with complementary mechanisms of action to improve glycemic control in type 2 diabetes patients, for example: Metformin and Glimepiride, Pioglitazone and glimepiride etc. FDC products of two or more analgesics with different modes of action activate multiple pain-inhibitory pathways and thus provide more effective pain relief, for example: Aceclofenac and Paracetamol, Diclofenac and Paracetamol etc. However some disadvantages are also associated with FDC products such as dosage alteration of one drug is not possible without alteration of the other drug, i. e. dose adjustment to the patient’s needs. Some FDCs when combined leads to increased toxicity, example, anti-TB drugs have the side effects oto and nephro-toxicity. If the biological half-life of different compounds in FDC is different, it may considerably affect the pattern of drug availability in the plasma, and hence the over all efficacy of the product is affected, example, Rifampicin FDC products [2-7].

Development of FDC Products

In relation to formulation development very similar principles apply to fixed dose combination finished products as apply to single entity products. However, there are additional complexities arising due to the presence of two or more drug substances. These complexities are related to compatibility of drug substances, assay, stability, physicochemical properties (for example dissolution rate) and bioavailability/bioequivalence, analytical methods and acceptance criteria for impurities, stress testing and determination of shelf lives of FDC products. Chemical and physicochemical compatibility of the APIs in an FDC with one another as well as with possible excipients. Physicochemical properties and stability of each of the drug in an FDC will define the formulation approaches to maintain stability during the shelf life of the combined drug product. For example, the hygroscopicity of one active drug substance can influence the stability of the other drug in the combination product unless they are completely separated by way of multiple techniques. On the basis of formulation strategy, the manufacturing of an FDC can be as simple as mixing the two or more active drug substances provided that they are physically and chemically compatible and stable with excipients required for encapsulation, or tableting and compression followed by coating or encapsulation. If the active drugs are incompatible with each other, they would need to be formulated in a single pill using a number of different options, such as multilayer tablets, compression-coated tablet, multiparticulates in capsules, combinations of coated and uncoated beads, or pellets of one placed with a powder of another active. The manufacturing process is more complex with bilayer, three-layer, or tablet-in-a-tablet manufacturing. This could involve multiple granulations and compressing these layers using suitable multilayer tablet presses or a special press for tablet in a tablet [1, 8].

Analytical method development for FDCs

Method development by HPLC-UV for two or more compounds and their related impurities becomes very complex if the UV profiles are not similar. Hence need to be analyzed by other sophisticated techniques such as LC-MS, UPLC-PDA, UPLC /Q-TOF-MS etc. Developing and validating a stability-indicating assay method becomes more challenging when multiple drugs are present in a drug product. Since developing and marketing new chemical entities (NCEs) for multiple indications is difficult task, pharmaceutical companies are looking into creating products by combining two or more known, compatible APIs to treat multiple diseases and achieve better patient compliance. Method development for two or more compounds and their related impurities becomes very complex if the solubility and the pKa values vary greatly and the UV profiles are not similar. If the solubility and the pKa values of the APIs involved are similar, where all the active components are totally soluble in water, the method development is much easier [9-11]. In the case of two APIs, new impurities seen in stability samples, the samples must be evaluated carefully and the impurities reported to their origins. For routine analysis in a stability program, a stability-indicating method is required for analyzing both the API and impurities. Analytical methods should be validated for each active ingredient in the presence of related process impurities and degradation products. The interference by degradation products can be controlled by peak purity testing by HPLC-UV, HPLC-PDA, HPLC-MS, UPLC-PDA and UPLC/QTOF techniques. The acceptance criteria for impurities in FDC products are expressed with reference to the parent active ingredient and not with reference to the total content of active ingredients. During stress testing, the active ingredients are combined in the same ratio as in the final product. The expiry date is determined on the basis of stability of the least stable active ingredient [12-17].

Regulation of FDC products

The Drug Controller General of India (DCGI) had given marketing approvals for 40 FDCs in January 2002. It is an accepted fact that FDC is treated as a new drug, because by combining two or more drugs, the safety, efficacy, and bioavailability of the individual active pharmaceutical ingredient (API) may change. As per the Drugs and Cosmetic Act, 1940, any new drug and the permission to market a drug is to be given by the DCGI. Before the approval of any drug, the Central Drugs Standard Control Organization (CDSCO) undergoes a process with respect to their quality, safety and efficacy. The DCGI monitors the drug formulations, including the combinations of drugs, from the angle of safety, effectiveness and rationality. In India, the CDSCO is the main controlling department for drug approval. The CDSCO regulates this process through DCGI. List of some marketed FDCs approved by DCGI is presented in Table 1. The DCGI controlling the drug regulations through drug commissioners and drug inspectors in different states of India. Recently CDSCO, adopted guidelines for industry on fixed dose combinations in April 2010. These guidelines provide the information about various aspects of formulation, manufacture and marketing of FDC products in India [8]. Internationally, there is an increasing trend to license fixed-dose combination products for the market. Currently there are no specific international guidelines for FDCs but WHO published the guidelines for registration of fixed-dose combination medicinal products in the year 2005. Some national authorities have developed their own guidelines, some for specific classes of medicines [1]. Guidelines for registration of FDCs products are summarized in Table 2.

Table 1. List of some marketed FDCs approved by DCGI

Guidelines	Description
Scientific and technical principles for FDC products. Botswana, 22 April 2004	Described the registration, quality, efficay, and safety requirements for FDCs.
Fixed-combination medicinal products. CPMP April 1996, CPMP/EWP/240/95, II/5773/94 formerly known as Testing combination; and licensing criteria for FDC products.	Require circumstances in which FDCs are acceptable, describe the considerations of pharmacokinetic and pharmcodynamic interactions, evidence for safety and efficacy.
WHO guidelines for registration of fixed-dose combination medicinal products. (Annex 5, 39th report). TRS No. 929, Geneva, 2005	Described the advantages, disadvantages, quality, safety and marketing authorization of FDCs.
Guidance for industry on fixed dose combinations (FDCs), CDSCO, New Delhi, April 2010	Guidelines to manufacture, import, and marketing approval of FDCs as per Drugs and Cosmetics Act and Rules.

Table 2. Guidelines for registration of FDCs products

Category	FDC products	Category	FDC products
Antihypertensive	Losartan + Hydrochlorothiazide tablets Valsartan + Hydrochlorothiazide tablets Telmisartan + Hydrochlorothiazide tablets Atenolol + Hydrochlorothiazide tablets	Hypercholesterolemia (Lipid lowering)	Atorvastatin + Ezetmibe tablets Simbastatin + Ezetmibe tablets
Antidiabetics	Glipizide + Metformin tablets Glimepiride + Metformin tablets Pioglitazone + Metformin tablets Pioglitazone +Glimepiride + Metformin tablets	Antitubercular	Isoniazide + Rifampicin tablets Isoniazide + Ethambutol tablets Isoniazide + Rifampicin + Ethambutol tablets
NSAIDS, Analgesic and antipyretic	Diclofenac + Paracetamol tablets Ibuprofen + Paracetamol tablets Aceclofenac + Paracetamol tablets	Antimalarials	Sulfadoxine + Pyrimethamine tablets Artemether + Lumefantrine tablets

CONCLUSION:

The FDC products provide the increased drug efficacy and improved patient compliance. Drugs in FDC products provide complementary mechanism of action to each other, therefore extended range of therapeutic effects can be achieved. Several pharmaceutical companies now investing for the development and marketing these products. The use of FDC products becoming worldwide, hence the systematic approach is required for the design, development and its regulations. For the development of FDC products several factors must be taken in to consideration such as Chemical and physicochemical compatibility of the drug substances in an FDC with one another as well as with possible excipients. Other factors are their stability, bioavailability, analytical methods, acceptance criteria for impurities and determination of shelf lives of FDC products. In the presented review article, advantages of FDC products have been discussed. Strategies for formulation development, analytical method development and regulatory guidelines for FDC products have been described in brief.

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Received on 21.05.2016 Modified on 15.06.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 207-210.

DOI: 10.5958/0975-4377.2016.00028.8