Pharma Voice

Multi-component drug delivery system: An emerging trend

Swarnlata Saraf and K Dashora give an overview of multi-component therapy, which is a way of increasing drug efficacy when a single drug fails

The concept of multi-component therapy is beneficial when the selected agents possess differing mechanisms of action that provide additive or synergistic efficacy. It reduces the required doses of individual agents compared with mono-therapy and limits side effects. Multi-component therapy may seem costlier than mono-therapy in the short term, but has significant savings, like lesser treatment failure rate, reduced case-fatality ratios, slower development of resistance, and consequently, less drug development costs. There are three general categories of multi-component therapy.

First category includes individual components like analgesic with antipyretic and beta-blocker with diuretic. The second category is to ameliorate the unwanted pharmacodynamic effects of the active agents like anti-cholinergic with narcotic. The third category includes combinations that improve pharmacokinetic properties like co-administration of levodopa and decarboxylase inhibitor which reduces the dopamine formation in GIT and outside CNS. Multi-component therapy is now in demand for its development regarding formulations as well as dosage designing. It has been proved for its effectiveness, affordability and acceptability of dosage regime for a variety of diseases like malaria, joint disorders, pain, hypertension and tuberculosis.

Malaria

It is estimated that 90 percent of global malaria mortality occurs in sub-Saharan Africa. The resistance to chloroquine has brought the efforts to control malaria in the region to a stand still. The resistance was first recorded in 1979 in East Africa, but has now been reported from almost all malaria endemic countries of Africa. Sulfadoxine-pyrimethamine (SP) was seen as the obvious successor to chloroquine. However, resistance to SP is developing quickly, thus reducing the therapeutic life of this drug. Artemisinin-based combination therapies have shown to improve treatment efficacy and also contain drug resistance in South-East Asia.

Combination therapy (CT) with anti-malarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. In the context of this definition, multiple-drug therapies that include a non-anti-malarial drug to enhance the anti-malarial effect of a blood schizontocidal drug are not considered combination therapy. Similarly, certain anti-malarial drugs that fit the criteria of synergistic fixed-dose combinations are operationally considered as single products. Neither of the individual components would be given alone for anti-malarial therapy as in the case of sulfadoxine-pyrimethamine.

Arthritis

Rheumatoid arthritis (RA) is a chronic and potentially crippling inflammatory disorder, which progressively wears away the bone and cartilage. Joint erosions are routinely seen within six months of RA's onset and occur rapidly, in the course of the disease. Moderate disability within two years of diagnosis is not uncommon. While conventional DMARD (disease-modifying antirheu-matic drug) therapies have been shown to slow joint destruction, they are powerless to stop RA's progression or reverse joint damage. In addition to early treatment, combination treatment with DMARDs, as well as, with biologic agents, has been shown to yield more favourable outcomes than a single treatment. The January 2006 issue of Arthritis & Rheumatism presents the first study to compare the effectiveness of DMARD therapy alone, anti-TNF (tumour necrosis factor) therapy alone and a combination of DMARD and anti-TNF therapy. The compelling results affirm the long-term benefits of early combination therapy for women and men afflicted with aggressive RA.

Pain

Pain of multiple etiologies remains a substantial problem for many patients. Improved pain relief can be demonstrated by multi-modal analgesic combinations. Substantial evidence supports combining analgesics for the management of pain and, in some instances, they have a heterogenous pharmacologic sparing effect. Fixed-dose combination analgesics with demonstrated efficacy and safety are widely useful for pain management. However, studies have to be done to explore the specific analgesics at specific doses that can be combined with a coanalgesic in a patient-specific manner to achieve additive, if not synergistic, multimodal pain relief with the fewest possible adverse consequences.

Hypertension

The first-line therapy for hypertension remains a betablocker or diuretic, given in a low dosage. A target blood pressure of less than 140/90 mm Hg is achieved in about 50 percent of patients treated with monotherapy; two or more agents from different pharmacological classes are often needed to achieve adequate blood pressure control. Single-dose combination anti-hypertension therapy is an important option that combines efficacy of blood pressure reduction and a low side effect profile with convenient once-daily dosing to enhance compliance. Combination anti-hypertensives include combined agents from the following pharmacological classes: diuretics and potassium-sparing diuretics, beta blockers and diuretics, angiotensin-converting enzyme (ACE) inhibitors and diuretics, angiotensin-II antagonists and diuretics, and calcium channel blockers and ACE inhibitors.

AIDS

Combination anti-HIV therapy is now the standard of care for people with HIV. It is sometimes called HAART (Highly Active Anti-Retroviral Therapy). There are now 17 anti-HIV drugs available by prescription. These anti-HIV drugs fall into three main categories:

• Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs), which include abacavir (Ziagen), lamivudine, 3TC (Epivir), tenofovir (Viread), abacavir/lamivudine /zidovudine (Trizivir), lamivudine/zidovudine (Combivir), stavudine, d4T (Zerit), didanosine, ddI (Videx, Videx EC), zalcitabine, ddC (HIVID), and zidovudine, AZT (Retrovir).
• Protease Inhibitors (PIs), which include amprenavir (Agenerase), nelfinavir (Viracept), saquinavir (Fortavase), indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase), and lopinavir/ritonavir (Kaletra).
• Non-nucleoside Reverse Transcriptase Inhibitors (NnRTIs), which include delavirdine (Rescriptor), efavirenz (Sustiva), and nevirapine (Viramune).

Studies clearly show that three drug combinations of these anti-HIV drugs are much more effective than one drug used alone or two-drug combinations in preventing disease progression and death. Numerous studies of triple drug combinations using either a PI or a NnRTI with two NRTI anti-HIV drugs, showed that the triple combination could greatly reduce disease progression and deaths in people with AIDS.

The name now commonly given to combinations of anti-HIV drugs is HAART. Recommendations from the National Institutes for Health and the Public Health Service state that the goal of anti-HIV treatment is to keep the level of HIV in the body as low as possible, for a relatively longer time. The best combination of anti-HIV treatments is not yet known for certain.

What the future holds

The future will also see the increasing application of multi-component therapy as a front-line defence against the disease, aiming at long-term corrective treatment through the designing of multi-component, novel, drug delivery system. During design of these formulations, several factors have to be considered, like careful pharmacokinetic parameters for dosage regimen to achieve a desired therapeutic efficacy of drug in the body. Thus, designing of such proper dosing services will minimises the drug toxicity, reduces the overdosing or drug complications, keep health care at minimum cost and ultimately increase the patient compliance.

(The writers are the faculty of Institute of Pharmacy, Pt Ravishankar Shukla University)