Pharmacokinetic advantages of valdecoxib in BCD over valdecoxib

OTHER DRUGS FORMULATED USING BCD

Betacyclodextrin has been used the world over to improve the water solubility of many other drugs. Examples include alprostadil, itraconazole, ziprasidone, dexamethasone, choramphenicol, and NSAIDs such as diclofena, nimesulide, piroxicam and rofecoxib. But for some molecules such as rofecoxib, the improvements in water solubility conferred by BCD have not been substantial. In a bioavailability study conducted to evaluate the benefit of formulating rofecoxib with BCD, investigators used 2 samples of rofecoxib and a sample of rofecoxib in BCD.

IMPROVEMENT IN Cmax

if a drug show high Cmax values, more amount of the drug will be available for distribution to target tissues, thus demonstrating better pharmacotherapeutic action. A study in 12 healthy volunteers compared the peak plasma concentration of valdecoxib alone and valdecoxib in BCD. The study results showed that valdecoxib in BCD achieved higher peak plasma concentrations of valdecoxib in BCD achieved higher peak plasma concentrations (204.82). In this study area under the curve (AUC)for valdecoxib in BCD was higher (1441.71 mcg.h/L)
the above study results prove that valdecoxib in BCD achieves peak plasma concentrations quickle and demonstrates higher peak plasma concentrations and AUC than valdecoxib alone.

IMPROVEMENT IN TMAX

The Tmax of a drug reflects how fast it can reach maximum concentrations in plasma. The faster a drug reaches peak plasma concentration, the faster will the drug show maximum therapeutic action. This is particularly important for drugs that relieve pain.
In crossover study of 12 healthy volunteers comparing the Tmax of valdecoxib in BCD vs valdecoxib alone, valdecoxib in BCD achieved maximum plasma concentration earlier than valdecoxib alone. The investigators found that valdecoxib alone reached peak plasma levels in 2.45 hours shown in figure

VALDECOXIB IN BCD-NOVEL FORMULATION FOR IMPROVED ACTION

As noted, valdecoxib is practically insoluble in water.its solubility can be improved by formulating it with a solubility can be improved by formulating it with a solubility enhancer, BCD. For the first time, this has been achieved by pharmaceutical chemists and formulation is found to be more water soluble than valdecoxib alone. In an in vitro dissolution study,valdecoxib in BCD scored over valdecoxib alone. Valdecoxib in BCD was 100% water soluble in 15 minutes, wheres valdecoxib alone was only 79% soluble in this time. These results have demonstrated positive effects of complexation with BCD on Tmax,Cmax and bioavailability.

BCD

The exterior face of the truncated cone of BCD is hydrophilic this facilitates solubilisation of the complex in the GI fluids by shielding the lipophilic guest molecule from the polar forces of water. Once in the gut lumen, the lipophilic guest molecule dissociates at the lipid membrane of the superficial lining cells. These lipids at the cell interface have greater affinity for the lipophilic guest molecule than does BCD. The librated guest molecule passes into the lining intercellular matrix, lymphatics, and capillaries.

Enhancing water solubility using BETACYCLODEXTRIN

Enhancing a drug’s bioavailabily has become a vital necessity in today’s pharmaceutical industry. As drug discovery moved in the direction of designing molecules often decreased to levels insufficiently addressed by conventional formulation methods. As a matter of facts, more than 40% of new chemical entities are insufficiently soluble to allow for acceptable dosage formulation. In the last decade, competition in the phsiocochemical properties of drugs and improving formulations to give the patient a better products. Cyclodextrins provide a drug delivery system capable of improving the solubility of poorly soluble drugs by their solubilising power. They have other advantages as well.Cyclodextrins have been known for about one hundred years. In the year 1953, the first patent on CDs and their complexes was registered, but until the 1970s, not much work could be done because they could not be manufactured in high amounts and in pure states. At present, a monograph for BCD is available in both the US Pharmacopoiea/National formulary and monographs for cyclodexterins are available in many compendia. Thus more than a country after their discovery, CDs are now recognised as important pharmaceutical Excipients.
Cyclodextrins are cyclic oligosaccharides composed of α D-glucopyranose units that have a relatively hydrophobic (water hating) central cavity and hydrophilic (water loving) outer surface. Betacyclodextrin is the most common among the CDs and consists of 7 glucopyranose units. Although represented on 2-dimensional paper as rings.BCD has an overall shape reminiscent of a hollow truncated cone. On account of its relatively hydrophobic interior . BCD has the ability to form inclusion complexes with lipophilic ‘guest molecules’.

Solubility

Valdecoxib below pH 9, is “practically insoluble” in water as defined by the United States pharmacopoeia classification system; its solubility increases with increasing temperature. Its water solubility is 9 mcg/ml at 250c at Ph 7. If its water solubility is increased, by suitable means, it may be possible for it to have faster dissolution in the GI fluids and faster absorption across the GI membrane. If the rate of absorption is quicker, then faster will be the ‘time for the drug to reach maximum concentrations in the blood’ (Tmax), and a possibility of higher ‘peak plasma concentrations at the Tmax’ (Cmax). Improvement in solubility characteristics of drugs exhibiting poor water solubility thus ultimately may translate into clinical benefits for patients.
This improvement in water solubility can be achieved using a solubility enhancer such as BCD.

Efficacy and safety

Valdecoxib is a new COX-2 inhibitor that has been approved for the acute and chronic treatment of the signs and symptoms of adult rheumatoid arthritis (RA) and Osteoarthritis (OA), and for relief of pain associated with primary dysmenorrhea. It has also been found to be effective as a postsurigical analgesic after oral and orthopaedic surgery. In all these indications, valdecoxib has been shown to be significantly more effective than placebo. In comparative studies, valdecoxib exhibits efficacy equivalent to that of naproxen in OA and RA symptom relief, and enhanced efficacy equivalent to that of naproxen in OA and RA symptoms relief, and enhanced efficacy to oxycodone and rofecoxib in food and oral surgery. Valdecoxib has been generally well tolerated in clinical trials with a similar incidence of adverse events to placebo.

Valdecoxib Betacyclodextrin

Treatment of pains is multifaceted and therapy is focused among multiple areas, on decreasing the subjective intensity and duration of the pain complaint, decreasing the potential for conversion of acute pain to chronic pain. A fast onset of action, and fast relief are the key requirements for drugs that are used to manage pain.

Generally, medications for pain relief are available in the form of oral dosage forms, and most commonly as tablets. The ultimate goal of tablet is to serve as a carrier for a drug to reach the blood stream for distribution to its sites of action. After oral ingestion, the drug contained within a tablet reaches the bloodstream in a series of steps. First, the tablet disintegrates in the gastrointestinal (GI) tract into fine particles under the influence of the digestive juices. Then, the drug gets dissolved in the GI fluids. Once the drug is present in the GI fluids in the form of a solution, it has the potential to be absorbed. Absorption occurs across the GI membrane by different mechanisms, chiefly by passive diffusion. Among these many steps, the slowest step that controls the overall rate and extent of appearance of intact drug in the systemic circulation is called the rate limiting step. This rate-limiting step may vary from drug to drug. Thus, for a drug that has a very poor aqueous solubility, the rate at which the drug dissolves in the GI fluids is often the slowest step and therefore exhibits a rate-limiting effect on the drug bioavailability. Improvement in the solubility characteristics of such a drug brings about faster solubility in the GI fluids and hence faster absorption and ultimately faster onset of action.

Valdecoxib, a newer cyclo-oxygenase-2 (COX-2) inhibitor, is “practically insoluble” in water (according to the united States Pharmacopoeia classification). Its aqueous solubility and, hence, dissolution can be increased by complexing it with Betacyclodextrin (BCD). Cyclodextrin (CDs)are cyclic oligosaccharides, which application, especially in improving water solubility of poorly soluble drugs, and improving bioavailability. Betacyclodextrin is one among the common natural CDs. Dissolution studies have shown that the more water soluble than valdecoxib alone. Thsis improvement in water solubility is reflected in improvements in C_max and T_max in human bioavailability studies. Thus, valdecoxib in BCD may have the potential to produce a faster onset of action which will benefit patients experiencing pain.