Christopher C. DeMerlis is a regulatory affairs manager at Colorcon, a division of Berwind Pharmaceutical Services, Inc., 415 Moyer Blvd., West Point, PA 19486, tel. 215.661.2766, fax 215.661.2778.

Christopher C. DeMerlis

	The US Food and Drug Administration has approved a substantially lower number of drug formulations containing new molecular entities (NMEs) in the past decade (1). In 2008, the agency approved formulations containing 21 NMEs and four biologics, slightly higher than the 2007 total of 17 NMEs and two biologics. The growth between 2007 and 2008, however, was not enough to counter the marked downward spiral of drug approvals during the past 10 years (1). Behind the trend may be tightening safety standards, the complexity of clinical trials that have escalated drug-development costs, and even perhaps a shift in emphasis as pharmaceutical companies move away from truly innovative solutions toward more complex therapeutic profiles. 

	An additional barrier to the development of new drug formulations is that, in some cases, active pharmaceutical ingredients (APIs) that show promising activity in animals or 

biologic systems fail to show sufficient efficacy in human clinical trials. In some cases, this discrepancy may be due to a lack of bioavailability and desired effect at the target site in the human body-properties potentially linked to the specifics of the formulation.

	The choice of excipients also can be a critical factor for developing clinically efficacious drug formulations. The current regulatory environment both inside and outside the United States, however, strongly discourages development of new excipients, limiting the choices to those already approved. The International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) has proposed specific regulatory changes to encourage new excipient development which, if adopted, could expand options for API formulation, potentially removing this formidable barrier to drug development. IPEC–Americas also developed an independent excipient review procedure, the IPEC Novel Excipient Safety Evaluation Procedure, which can serve as a temporary solution to this issue until the council's proposals are implemented. These efforts resulted in the evaluation of at least one novel excipient, Solutol HS 15 [Polyoxyl (Macrogol) 15 hydroxystearate manufactured by BASF, Ludwigshafen, Germany). The development of procedures for independent safety evaluation and its application to Solutol HS 15 are described in subsequent sections of this article.

	There is considerable activity in the development of new and innovative excipients (2, 3), including excipients for orally disintegrating tablets and controlled-release formulations. In the future, the application of nanotechnology may be evaluated for developing novel excipients for new therapeutic solutions. In many cases, these excipients will never be included in drug products under development because the regulatory risks under the current system are simply too great.

	In the long term, new paradigms are needed to evaluate excipient safety. The FDA guidance on the safety evaluation of excipients details safety tests generally required to establish safety of a novel excipient, which are strikingly similar to those required for a new drug (4). However, unlike drugs, excipients are designed to be pharmacologically inactive and these tests may be excessive for safety evaluation, thereby representing a potential barrier to innovative development of new excipients.

Current regulatory status of new excipients

	Under the current paradigm, even though excipient innovators are able to adapt to new procedures and are willing to invest in development and safety-evaluation costs, novel excipients are not finding their way into drug products. Understandably, drug-product manufacturers are risk-averse because of the large investments required for drug development. Despite these challenges, the expanding FDA Inactive Ingredient Database (IID) suggests that the demand for new excipients is strong. The IID lists excipients used in approved drug products, their route of administration, and their maximum dosage (i.e., maximum potency per dosage unit). A regulatory system with a strong, predictable excipient safety and efficacy evaluation could potentially lead to an explosion of new choices for drug formulators.

	Under current drug approval processes, novel excipients are not independently evaluated; they are only reviewed in the context of the first drug application containing the excipient. There is no regulatory approval process specifically for a new excipient as a unique molecule. Globally, the International Conference on Harmonization (ICH) does not have specific excipient safety evaluation guidelines, but FDA guidance on excipient safety evaluation cites several ICH safety-testing guidelines (e.g., ICH S1A, S2B, S3A, S5A, S7A and M3) as reference materials for the conduct of safety tests (4).

	According to FDA and ICH definitions, an excipient is considered "novel" if it is used for the first time in a human drug product. Although FDA maintains the IID, none of the US nor ICH standards distinguish between new chemical entities and minor modifications of approved excipients, coprocessed mixtures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for use in foods or cosmetics. Some of these excipients may not require the full battery of tests listed in the FDA guidance on excipient safety evaluation (4). In these cases, excipient and pharmaceutical manufacturers must predict what the reviewing agency will require upon review of the drug application. If the manufactuer is wrong, the consequence could be significant delays in drug approvals or rejection of the drug application. Most drug manufacturers are wary of this process and therefore rely on excipients already used in approved drug products for their formulation needs.

	In 2007, the IPEC–Americas Safety Committee proposed and developed the IPEC Novel Excipient Safety Evaluation Procedure, which is an independent excipient review procedure. This process was anticipated to reduce the cost and uncertainty related to the use of novel excipients in pharmaceutical formulations, thereby encouraging their use in drug-development programs and providing a needed boost to drug formulation innovation.

	The Aclairo Pharmaceutical Development Group (Aclairo PDG, Vienna, VA) manages the Novel Excipient Evaluation Committee (NEEC), an independent expert group of IPEC charged with conducting the safety evaluations of new excipients. The committee has successfully evaluated one excipient, Solutol HS 15, and is in the process of reviewing others. Two authors of this paper (R. Osterberg and W. Brock) serve on this expert committee.

The development of a regulatory strategy for novel excipient review has been an IPEC–Americas priority since the organization's inception in the early 1990s. At that time, the IPEC–Americas Safety Committee held a series of meetings that culminated in a publication of recommendations for excipient-safety testing based on route of administration (5). In 2002, the chairman and deputy chairman of FDA's Center for Drug Evaluation and Research (CDER) Inactive Ingredients Subcommittee published a proposal for excipient safety review largely based on the IPEC recommendations (6). The agency proposal was finalized in 2005. The ICH M3 document on nonclinical safety studies for conducting human clinical trials is also relevant in this context (7).

	In August 2005, IPEC–Americas presented a proposal for an independent excipient evaluation procedure to FDA staff. FDA agreed to review the first excipient-safety evaluation expert committee submission for consistency with FDA procedures. Over the next two years, the IPEC Safety Committee convened the expert committee, developed procedures, and solicited the first submission. In September 2007, the expert committee reviewed the safety package for Solutol HS 15 and submitted their conclusions to the sponsor. In May 2008, in a letter to IPEC, FDA concluded that, "The issues considered by the expert committee reviewers in the weight-of-evidence determination on the safety of Solutol HS 15 are the same as would be considered by a reviewing division," indicating that the IPEC process provides a reasonable proxy for FDA review.

NEEC's primary function is to evaluate compliance of excipient data with the FDA guidance on safety evaluation and to make recommendations to the excipient manufacturer if data gaps are noted in the excipient dossier. The expert committee acts independently of the IPEC-Americas Safety Committee and its members must have confidentiality agreements in place. NEEC is comprised of three experts in general toxicology and, ideally, members have experience in industrial, academic, or regulatory toxicology, including experience in toxicology laboratories. Committee members may rotate off the committee every two to three years to provide new expertise to the process. If the committee decides that an expert in one facet of toxicology is needed to help in decision-making, a request to the excipient manufacturer will be made for permission to include the expert in the deliberations. This expert must also sign a confidentiality agreement. Aclairo PDG administers this review procedure.

	An excipient safety dossier in common technical document (CTD) format (to facilitate subsequent FDA review) is submitted to Aclairo PDG who sends it to the expert committee chairperson, who in turn distributes it to other committee members. Review times will depend upon the quantity of the information within or absent from the dossiers but are anticipated to take one to three months; in most cases, costs will not exceed a total of 50 hours of review plus administrative overhead. The chairperson or a designee collates the comments of the committee members and writes a draft report that will be sent to each member for concurrence or further discussion. Once agreement is reached, the final draft is sent to the excipient sponsor for review and comment. If the expert committee cannot reach agreement on one or more points in the final draft, the sponsor is told about the disagreements and the reasons for them. The sponsor may discuss the final draft with the expert committee, request clarifications or explanations and when satisfied, the final report is signed by the chairperson and sent to the sponsor who is the sole owner of the committee report. The committee report will contain at a minimum:
	1. A discussion of chemical and toxicological data and human safety concerns based upon intended use of the excipient
	2. Opinions on conformance with data needs according to the FDA guidance on safety evaluation for excipients
	3. Identification of any data gaps
	4. Points of reviewer disagreement if not resolved with the reasons identified in the final draft.

The expert committee's review of Solutol HS 15

	BASF novel excipient, Solutol HS 15, a non-ionic solubilizer, was developed to fulfill an unmet need for a safe and effective excipient for parenteral and solid oral dose formulations containing poorly soluble APIs. Chemically, Solutol HS 15 is composed of polyglycol mono- and di-esters of 12-hydroxy-stearic acid and contains approximately 30% polyethylene glycol. Solutol HS 15 is listed as Macrogol 15 hydroxystearate in the 

. The excipient has been used in approved drugs in some countries, including Canada and Argentina. Even though the Solutol HS 15 drug-master file (DMF) was filed with FDA in January 1992 (DMF #9501), it has not yet been used in FDA-approved drugs because of its novel excipient nature and absence of FDA-review status.

	In 2007, IPEC–Americas Safety Committee Chair Jay Goldring, recognizing the urgent industry need for an excipient that meets the requirements in formulations containing poorly soluble APIs, selected Solutol HS 15 solubilizer as the subject for the first NEEC review. The expert committee's report would then be reviewed by FDA for consistency with its own review process.

	As defined in the IPEC–Americas procedure in the previous section of this article, BASF entered into an agreement with Aclairo PDG to develop an independent safety evaluation of Solutol HS 15. To accomplish this, BASF prepared a package of information containing safety and chemistry information. The package included the following items:

		Technical information containing a summary of chemistry, manufacturing, and controls (CMC) information

		BASF's safety expert report on Solutol HS 15

		Reports of all acute, subchronic, reproductive, and genotoxicity studies conducted by BASF for Solutol HS 15 under different routes of administration

		Safety evaluation assessment report for Solutol HS 15 conducted by the European Medicines Agency

		Safety expert report of a related BASF solubilizer excipient Cremophor (Polyoxyl 35 Castor Oil: 

		FDA IID information for use of Cremophor in 15 FDA-approved drugs

		List of other excipients with related chemistry derived from the FDA IID.

	The package also included a cover letter requesting that Aclairo PDG evaluate the information submitted and provide an independent safety evaluation for Solutol HS 15.

	The independent safety evaluation procedures were coordinated and led by Dr. Osterberg. Aclairo conducted an independent safety assessment using two other distinguished toxicologists. The six-month evaluation implemented all the steps of the review process described above. At the conclusion of the process, the expert committee issued an independent safety evaluation of Solutol HS 15 to BASF.

	Following this process, BASF submitted a package to the IPEC–Americas Safety Committee Chair. This package included a cover letter from BASF that requested review and consideration for submission to FDA under the IPEC Novel Excipient Safety Evaluation Procedure, a safety expert report from Aclairo PDG and all the documents submitted to Aclairo PDG outlined in the previous paragraphs in this section. The BASF submission was forwarded to FDA by the IPEC-Americas Safety Committee. FDA provided its review letter of Solutol HS 15 to the committee which then informed BASF of the agency's findings.

	After receiving feedback, BASF approached the United States Pharmacopeia (USP) for consideration of an official monograph for Solutol HS 15 on the following grounds: FDA review of this excipient, monograph status in 

, and use in approved drugs in some countries outside the US. USP informed BASF that, as required by their procedure for development of official monographs, they consulted the compendial group at FDA. USP then requested that BASF submit materials for monograph development. Efforts by BASF and USP led to the publication of Polyoxyl 15 Hydroxystearate (Solutol HS) 

 monograph in the January/February 2009 issue of the USP 

Excipient safety evaluation: a new paradigm

	Excipients received a great deal of notoriety in the early 1930s. At that time, a chemist at the Massengill Company used diethylene glycol (DEG) as a sweetening agent for elixir of sulfanilamide as the "teaspoon of sugar to help the medicine go down" because the elixir was somewhat sour for use in children. A principle in toxicology introduced by Paracelsius about 500 years ago was "

Omnia venenum sunt, nec sine veneno quicquam existit; dosis sola fcit ut venenum non sit

," which, literally translated, states that "all substances are poisons; there is none which is not a poison." This concept continues to be a basic tenet in the field of toxicology. The Massengill Company at the time had not completely investigated the potential toxicity of DEG. Hence, many children fell ill to the kidney toxicity associated with this compound, and many of those children unfortunately died (8).

	Based on this tragic incident, the 1938 amendment to the Food, Drug, and Cosmetic Act was promulgated, essentially requiring that the safety of a drug be demonstrated before marketing. In spite of this regulation in the US and the incident that occurred in the 1930s, additional incidents of DEG contamination occurred internationally in the 1980s and 1990s. An important consideration with regard to these incidents, however, is that the safety of the drug substance was not in question, but rather the safety of the excipient had not been demonstrated before use in the drug-product formulation.

	Indeed, the regulatory environment for the approval of excipients has not kept pace with the innovations observed in the pharmaceutical industry. Except as associated with the submission of an NDA for a new pharmaceutical that contains an innovative excipient, there is no regulatory process for the independent approval of the excipient.

	During the past two decades, regulatory allowance of an excipient occurred only through the use of the material in a drug-product formulation. Hence, with approval of the drug product came acceptance of the excipient (excipients are not approved but their use is allowed). That excipient could be used subsequently in other drug products up to the concentration and duration used in the previously approved drug formulation. Moreover, the excipient could be used in a new drug product for a different route of administration only if toxicology data generated 

 that route was accepted by FDA. P. Baldrick proposed that a guidance was urgently needed for excipients, and further suggested that this would be a useful topic for ICH consideration (9). This suggestion was not a new concept as several years before, Steinberg et al. proposed a testing scheme for the evaluation of new excipients and that testing scheme was ostensibly similar to that used in the evaluation of a new drug substance (5). In that paper, the authors described a nonclinical program for excipients based on the oral route of administration because most drugs are approved for oral use.

	Baldrick's paper was followed by several publications, each further indicating the need for a regulatory process for excipients as well as a proposal for how to manage new excipients. In 2003, G. Pifferi and P. Restani suggested that new excipients be evaluated much in the same way as food additives (i.e., by the International Toxicological Committees such as the Joint Expert Committee on Food Additives, a committee of the World Health Organization) (10). The authors demonstrated that there are a large number of substances that can be used as excipients with a very diverse chemical profile, sources, technological functions, and so forth. The Pifferi/Restani paper of 2003 followed a 1999 paper describing the need for standards of characterization and quality review, just one more aspect needed for a regulatory framework for excipients (11).

	Also in 2003, at the American College of Toxicology annual meeting, a symposium on issues associated with food and excipient safety was presented (12). M. Steinberg and I. Silverstein reviewed several concepts for addressing the regulatory status of new excipients but clearly noted that there was no regulatory process in the US compared with what had been established in Europe and Japan (13). Osterberg and N.A. See subsequently described the testing paradigm of what had been recently published draft guidance from FDA on excipient testing. In that guidance, which was subsequently approved (14), the various toxicity studies needed for a new excipient are outlined.

	Overall, the guidance is similar to what Steinberg et al. had proposed several years earlier in 1996 (5), although the provision for safety pharmacology studies was included in the FDA guidance. Regardless, a provision for a stand-alone regulatory process remained elusive. As described above, IPEC–Americas established an expert working group to review the safety of new excipients based on testing, and proposed to FDA that the studies represent good science and excipients should be allowed in drug products without going through a regulatory process in conjunction with a drug approval. Because of the absence of a regulatory process, the innovation of new excipients has been restricted. Moreover, because of the costs associated with a standard toxicity program for a new excipient, innovation and development have been limited (see Table I).

The IPEC program described is a typical toxicology program with costs based on 2009 pricing of studies within the contract research organization (CRO) industry. Moreover, the costs reflect a basic study design and do not include toxicokinetic assessment which could add about 5–10% of the total cost. In addition, to initiate the 90-day studies, shorter-term repeat-dose studies would be needed to assist in setting dose levels. The added costs for these studies could approach $200,000. Finally, the costs associated with this program do not include discovery, development, and manufacturing costs for the new excipient.

	The undertaking of a toxicology program represents a risk to a business, but in the current regulatory environment, such a program is needed. There remains an option to the excipient development process that does not require such an outlay of resources early in the development phase. Lessons learned from the drug discovery and development process may be helpful in toxicological screening of excipients for use with active pharmaceutical substances.

In the developmental toxicology program, 

 assays are used to screen for potential toxicity before undertaking more expensive toxicity tests. In this process, a compound that causes an undesirable toxicity can be eliminated from consideration. This "discovery" program leads to less cost and allows for a more rapid screening of multiple compounds to select those that represent potential utility as an excipient. In addition, the discovery program can be developed into different tiers of testing (i.e., as the compound is developed, additional testing is undertaken to further determine the potential safety of the compound).

	In the first tier, a compound is subjected to different 

assays to determine the potential genotoxicity, cytotoxicity, and metabolism and the ability of the compound to be absorbed across biological membranes. At the outset, however, it is recommended that a quantitative structure-activity relationship (QSAR) model be developed. A QSAR model enables the prediction of various toxicities based on structural similarity to existing chemicals. Hence, compounds can be easily limited from consideration if structural alerts for certain endpoints are revealed (e.g., carcinogenicity). There are several QSAR models that have been developed over the years, each with its own advantages and disadvantages. The model overall is useful for predicting potential toxicity for potentially allowing the use of short-term bridging studies that could be used to determine the toxicity of the new excipient compared with an excipient that has a more robust database.

	Following QSAR, it is recommended that the compound be subjected to 

 genotoxicity and cytotoxicity assays. These studies are comparably inexpensive to the longer-term 

toxicity studies. A cytotoxicity assay is valuable to determine the potential for the compound to cause cell disruption, and such a study is particularly useful if the compound would be administered intravenously. In addition to these 

 metabolism study can be done as a screening assay to determine the extent of metabolism and whether potential reactive metabolites would be formed. Finally, membrane penetration studies would be conducted. Ideally, the excipient would not be absorbed across biological membranes, but may enhance the penetration of API. Immunotoxicity studies would be done only if there is an important structural alert or the compound is from a class of excipients that may be known to induce an immunotoxic effect.

	If the data developed in this first phase of the program reveals limited or no concern for toxicity, then the compound is tested in repeat-dose toxicity studies with the idea that these additional tests will be compliant with FDA guidance for excipient testing. In the second phase, data could be developed that would allow the sponsor to "bridge" to existing, structurally related compounds. In this case, for example, a repeat-dose toxicity study would be conducted with a new pegylated substance based on the extensive toxicity data that exists for PEG-400. In this manner, the sponsor would not necessarily need to conduct studies if the data demonstrate a similar toxicity profile. In addition, in the repeat-dose study, groups of animals (rats) could be included to examine for potential reproductive and developmental toxicity following the Organization for Economic Cooperation and Development's Guideline 422. Finally, as part of the subchronic study, a micronucleus assay can be incorporated rather than conducting a separate study.

	One issue that arises as part of this second phase is conducting the studies in a rodent and non-rodent species. Indeed, it would be recommended that a separate study in, for example, the dog, be conducted. If long-term toxicity studies in the non-rodent species have not been conducted with the structural analog, then the sponsor will need to conduct at least a 90-day study.

	Based on the results of the second phase of the program, the sponsor would then conduct studies in a third and final phase of the program. In this final stage of excipient development, many of the studies outlined in FDA's excipient testing guidance would be conducted (e.g., safety pharmacology). More thorough metabolism studies also would be conducted in this phase. These studies can be complex depending on the compound. For polymeric materials, these studies may not be possible although a consideration for undertaking metabolism studies with the monomer or oligomers of the polymer would provide useful data on absorption and distribution. Based on the outcome of testing in phase two, definitive developmental and reproductive toxicity studies may be warranted. For developmental studies, a second species (e.g., rabbit) would be necessary.

Undertaking a toxicology program in accordance with FDA's excipient guidance leads to significant costs (see Table I) compared with the costs associated with alternative paradigm (see Table II). Because of the absence of a regulatory process, the timing to gain FDA acceptance can be very prolonged, particularly if the sponsor of a drug product uses a new excipient in the formulation and in nonclinical testing of the drug product. Although the process described here is no panacea for approval, this tiered process will permit the excipient sponsor to plan a program in conjunction with the drug product sponsor and thereby avoid toxicological surprises.

	The program outlined herein considers typical excipients. With the advent of biotechnology derived pharmaceuticals, new excipients for biotechnology drugs becomes a program development issue. How these new excipients would be examined in toxicology programs is yet to be determined. Moreover, with increasing emphasis on nanotechnology, these materials potentially represent new processes for drug delivery. Safety assessment of nanotechnology products is in its infancy, and how these materials will be evaluated remains to be determined as well. Finally, the outline of this tiered approach has not been a consideration by FDA, although a tiered-testing rationale is part of several regulatory guidance documents (e.g., metabolite testing, ICH Q3b impurity qualification). Hence, how the regulatory agency and, more importantly, API sponsors, will accept such an approach remains to be seen. Regardless, excipient sponsors should consider such an approach because it will limit cost and could advance a new excipient in a timelier manner.

 is a manager of regulatory affairs at Colorcon, Inc., 415 Moyer Blvd., West Point, PA 19486, CDeMerlis@colorcon.com. 

, is prior director of toxicology at Wyeth Consumer Healthcare, 

, is a manager of regulatory affairs at BASF Corporation, 

, is principal of Brock Scientific Consulting, and 

, is a senior consultant of pharmacology/toxicology at Aclairo PDG. For specific information about IPEC's procedure, contact Dr. Osterberg, tel. 703.506.6760, ext. 302, ROsterberg@aclairo.com

	*To whom all correspondence should be addressed.

Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients

Draft Guidance for Industry: Nonclinical Studies for the Development of Pharmaceutical Excipients

Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

	11. G. Pifferi, P. Santoro, and M. Pedrani,

Articles

The authors, representing the International Pharmaceutical Excipients Council, propose a new evaluation procedure, including tiered toxicology testing for excipients.

Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure

Making drug-embedded matrix tablets through the direct compression of a blend of drug, retardant material, and additives is one of the simplest formulation approaches. The inclusion of polymeric materials in a matrix system is a common method of modulating drug release (1). Drug-release retarding polymers are the key performers in matrix systems. Various polymers have been investigated as drug-retarding agents, each presenting a different approach to the matrix system. Based on the features of the retarding polymer, matrix systems are usually classified into three main groups: hydrophilic, hydrophobic, and plastic. Hydrophilic polymers are most suitable for retarding drug release, and interest is growing in using these polymers in sustained drug delivery (2–4). 

In India, natural gums and mucilage are well known for their medicinal use. Natural gums and mucilage are preferred to semisynthetic and synthetic excipients because of their lack of toxicity, low cost, availability, soothing action, and nonirritant nature (5–8). Many natural materials are studied for use in sustained-release tablets. These materials include: guar gum (9), ispaghula husk (10), olibanum and its resins (11), cross-linked high amylose starch (12), 

 (slippery elm mucilage) (13), pectin (14), 

dry plant extract (15), galactomannon from 

 (20), Tamarind seed gums (21), and gum copal and dammar (22).   

has not been explored as a pharmaceutical excipient. 

family is also known as the shoe-flower plant, China rose, and Chinese hibiscus. The plant is available in India in large quantities, and the leaves contain mucilage (23, 24). The leaves are used in traditional medicines as emollients and aperients to treat burning sensations, skin disease, and constipation (25). The plant contains cyclopropanoids, methyl sterculate, methyl-2-hydroxysterculate, 2-hydroxysterculate malvate, and β-rosasterol. Mucilage of 

 contains L-rhamnose, D-galactose, D-galactouronic acid, and D-glucuronic acid (26). The leaves contain carotene (7.34 mg/100 g of fresh material) and are used as cattle feed (27). The leaves also contain moisture, protein, fat, carbohydrate, fibers, calcium, and phosphorus (28). 

The objective of this study was to extract mucilage from the leaves of 

 and examine the various pharmaceutical properties of the dried mucilage to assess its functionality as an excipient. Specifically, the study  evaluated the physicochemical properties and examined the effect of polymer blends on the rate and kinetics of diclofenac sodium released from matrix tablets.  

Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug. Diclofenac sodium rapidly dissolves in intestinal fluid, reaches its maximum blood concentration (

max) within 30 min, and is metabolized mainly by hepatic hydroxylation and subsequent conjugation (29). In healthy human volunteers, the mean plasma clearance of diclofenac sodium was 16.0 L/h, and the mean elimination half-life of the terminal phase was 1.2–1.8 h (30). To reduce gastrointestinal irritation, a common problem with all nonsteroidal anti-inflammatory agents, effective enteric-coated dosage forms have been developed. Food delays the absorption of the drug, which  causes a nonreproducible pharmacokinetic profile, and the drug has no immediate therapeutic effect (31).  

Drug release from hydrophilic matrices is a complex interaction between dissolution, diffusion, and the erosion mechanism. In this study, the drug-release mechanism was evaluated for diclofenac sodium tablets prepared with highly hydrophilic mucilage from the leaves of

  full factorial design was carried out to evaluate the effect of certain variables such as the amount of mucilage and diluent. Further studies were performed using water uptake, the mass loss of pure mucilage, and the matrix tablet containing the drug and mucilage. A stability study for an optimized batch was performed for three months. 

Diclofenac sodium was received as a gift from Beacon Pharmaceuticals (Ahmedabad, India). The leaves of 

 were collected from the medicinal garden of the C.K. Pithawala Institute of Pharmaceutical Science and Research in Surat, India. Guar gum 

  (IP) grade, ispaghula husk, sodium carboxymethyl cellulose IP, lactose IP, talc IP, and magnesium stearate IP were received from Atul Chemicals (Anand, India). All other solvents and chemicals were of analytical-reagent grade. Deionized double distilled water was used throughout the study. 

 were collected, washed with water to remove dirt and debris, and dried. The powdered leaves were soaked in water for 5–6 h, boiled for 30 min, and kept aside for 1 h for complete release of the mucilage into water. The material was squeezed from an eight-fold muslin cloth bag to remove the marc from the solution. Acetone was added to the filtrate to precipitate the mucilage in a quantity of three times the volume of the total filtrate. The mucilage was separated, dried in an oven at a temperature  < 50 °C, collected, dried-powdered, passed through a sieve (number 80), and stored for further use in desiccators (32). 

Physicochemical properties of dried powdered mucilage. 

Dried- powdered mucilage was studied for percentage yield, particle size, mass loss on drying, viscosity, swelling index, bulk density, angle of repose, and compressibility.  

 The microscopic method was used (in triplicate) to determine the particle size of the dried mucilage.  

 The mass loss on drying was determined for an appropriate quantity of dried mucilage at 105 °C for 2 h in a hot-air oven. 

 The study was carried out in a 100-mL stoppered graduated cylinder. The initial bulk volume of 1 g  of dried mucilage was measured, and water was added in sufficient quantity to yield a 100-mL uniform dispersion. The sediment volume of the swollen mass was noted after 24 h in storage at room temperature. The swelling ratio was calculated by determining the ratio of the swollen volume to the initial bulk volume. The swelling ratio was evaluated in distilled water, simulated gastric fluid (0.1 N HCl), and phosphate buffer (pH 6.8) (33). 

  Rheological studies of dried mucilage were carried out using various concentrations of solution (0.1–0.5% weight/volume (w/v) in distilled water. The viscosity was measured using an Ostwald viscometer and compared with the viscosity of sodium carboxymethylcellulose.  

 A preweighed and presieved quantity of dried mucilage was poured into a graduated cylinder, and the volume recorded. The cylinder was tapped until the powder bed volume reached a minimum value, and the tapped volume was recorded. The bulk and tapped densities were calculated. Carr's index and Hausner ratio. Carr's index and Hausner ratio were calculated from the bulk and tapped densities.  

  The angle of repose (θ) was determined using the fixed-height funnel method and calculated as follows:  

is the radius of the powder heap. Comparisons were made between dried mucilage, guar gum, and ispaghula husk. 

Preparation of diclofenac sodium tablets. 

The required quantities of diclofenac sodium and dried mucilage powder (sieve number 80) were physically admixed. Lactose was included in the nine batches of factorial design. The powder blend was lubricated with 1% w/w talc and 2% w/w magnesium stearate. Lubrication was performed in a glass jar for 2 min. Each tablet contained 100 mg of the drug. The tablets were prepared by direct compression on a rotary tablet press (Rimek II, Karnavati Engineering, Ahmedabad, India) and fitted with concave punches of 9 mm in diameter. The turret was rotated at a fixed speed of 30 rpm (34). 

Hardness was determined by using the Monsanto hardness tester, and friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (Model EF2, Electrolab, Mumbai, India) for 4 min at 25 rpm. The tablets were dedusted, and the loss in weight caused by the fracture or abrasion was recorded as the percentage friability.  

 The weight-variation test was performed. Twenty tablets were weighed individually, and the average weight was calculated.  

The drug-release study was carried out using an USP XXIII paddle apparatus at 37 ± 0.50 °C at 50 rpm using 900 mL of distilled water and phosphate buffer (pH 6.8) as the dissolution medium (n = 5). A 5-mL sample solution was withdrawn at predetermined time intervals, filtered through a 0.45-μm membrane filter, diluted suitably, and analyzed spectrophotometrically at 276 nm using a UV-visible double-beam spectrophotometer (Shimazdu-UV 1700, Shimazdu, Kyoto, Japan). Equal amounts of fresh dissolution medium were replaced immediately after withdrawing a test sample. The percentage of drug that dissolved at different time intervals was calculated using a regression equation generated from the standard curve. Drug release from the optimized batch (HL6) and a market preparation of the drug were studied in distilled water. 

  randomized full factorial design was used. Two factors were evaluated, each at three levels, and experimental trials were performed at nine possible combinations. The ratio of mucilage (

) were selected as independent variables. The time required for 80% drug dissolution (

) and percentage drug released in 60 min (

Hydration capacities and erosion studies. 

  Erosion and water uptake of the formulated tablets were determined under conditions identical to those previously described for dissolution testing. Water uptake and mass loss were determined gravimetrically according to the following equations (35):   

Three tablets were used per time point. At predetermined times, the ring-mesh assemblies supporting the partially hydrated tablets were carefully removed, and the tablets were lightly blotted with tissue paper to remove excess surface water. After determining the wet weight, the tablets were dried at 70 °C for one day before reweighing to determine the remaining dry weight. The test was performed at speeds of 50 and 100 rpm. Placebo tablets consisting of pure mucilage were tested in the same way. All studies were performed in triplicate. 

Radial and axial swelling of the tablet. 

 The initial diameter and thickness of the tablet were measured, and the tablet was  kept in dissolution media. The increase in diameter and thickness was measured at various time intervals. To evaluate the relation, the equilibrium degree of swelling (

) was calculated from the radial and axial swelling ratio using the following equation: 

 drug release, the stability study of the best formulation (HL6) was carried out at 40 °C and 75% relative humidity in a humidity oven. Samples were withdrawn after a three-month interval, and 

Various physiochemical characteristics of the extracted mucilage from 

 were investigated. The percentage yield was 15%, and the average particle size was 180 μm. The mass loss on drying indicated the amount of moisture present in the material that was available to interact with other material. For dried mucilage, the mass loss on drying was 10.61%. The swelling ratio of mucilage was 9 in distilled water, 10 in simulated gastric fluid (0.1 N HCl), and 9 in phosphate buffer (pH 6.8). The authors  concluded that the swelling of mucilage is pH-independent, and the mucilage is nonionic. 

Table I:  Rheological data of  dried-powdered mucilage and sodium carboxymethylcellulose (CMC). 

The viscosity of the extracted dried mucilage was compared with that of semisynthetic polymer sodium carboxymethyl cellulose (see Table I). When dried mucilage concentration exceeded 0.2% w/v, the viscosity was very difficult to measure with the Ostwald viscometer. The dried mucilage had higher viscosity than the sodium carboxymethylcellulose. 

Table II:  Flow properties of dried-powdered mucilage and other gums.  

The flow properties and compressibility of the dried mucilage, including bulk and tapped density, Carr's index, Hausner ratio, and the angle of repose were assessed and compared with those of guar gum and ispaghula husk (see Table II). The angle of repose of a powder provides an insight into the magnitude of the cohesiveness of the powder and hence, its flowability. Mildly cohesive powders have angles of repose between 40° and 60° when measured by standard methods. Dried mucilage has an angle of repose of 27.83°. Guar gum and ispaghula husk have an angle of repose of 42.27°and 38.79°, respectively. From these results, the authors infer that the dried mucilage powder was less cohesive and had superior flow property. The Hausner ratio previews the degree of densification that could occur during tableting: the higher the ratio, the greater the propensity of the powder to densify. This phenomenon may produce tablets that lack uniformity of weight and content. The dried mucilage has excellent flow properties compared with those of guar gum and ispaghula husk. Dried mucilage, therefore, has flow properties suitable for use in a direct-compression formulation. 

Table III: Formulation of tablets and Y60, Y300, and t80 of preliminary batches. 

The average crushing strength of the prepared tablets was 4.8 kg/cm

 , a value which shows good strength. The friability was < 1% (i.e., between 0.75 and 0.91%). Tablets prepared from dried-powdered mucilage that passed the standard for uniformity in weight indicate homogenous drug content. These results show that tablets prepared from dried-powdered mucilage can be used as a directly compressible vehicle because of good hardness, low friability, and tablet-weight uniformity.  

Table IV: Formulation and dissolution characteristics of batches in a 32 full factorial design. 

Table III shows the composition of the preliminary batches (L1 to L3) and the results of their dissolution studies. Table IV shows the composition of the nine batches of the factorial design and the results of their dissolution studies. When the dissolution study of the preliminary batches was performed, the complete drug release was obtained within 9, 10, and 11 h with different proportions of mucilage and 100 mg of diclofenac sodium (see Table III). The authors concluded that mucilage is suitable as a sustained-release matrixing agent for a diclofenac sodium tablet. Four criteria were established for the desired drug-release profile:   

A release of 20–25% of the drug within the first hour.

Prolonged drug release of the remaining drug followed during 12 h, preferably at a relatively constant rate

The time to release 80% of the drug was 490 < 

  full factorial design was constructed to study the effect of dried mucilage powder (

) on the drug release of the diclofenac sodium tablets. The dependent variables chosen were 

 (i.e., the percentage of drug released in 60 and 300 min, respectively and the time to release 80% of the drug). The following statistical model incorporating interactive and polynomial terms was used to evaluate the response: 

  is the arithmetic mean response of the nine runs, and b

is the estimated coefficient for the factor 

) represent the average result of changing one factor at a time from its low to high value. The interaction terms (

) show how the response changes when two factors are simultaneously changed.  

 values for the nine batches (HL1 to HL9) showed a wide variation: 22.38 to 34.00%, 52.75 to 69.33%, and 388 to 547 min, respectively. The data (see Table IV) clearly indicate that the values are strongly dependent on the selected variables. The fitted equation relating the response 

 to the transformed factor is shown in equations 6–8:  

The values of the correlation coefficient were 0.9879, 0.9831, and 0.9870, respectively, indicating a good fit. Equations 6 and 7 may be used to obtain a reasonable estimate of the response because a small error of variance was noticed in the replicates. The polynomial equation can be used to draw conclusions after considering the magnitude of the coefficient and the mathematical sign it carries (i.e., positive or negative). The data demonstrate that both factors (

 of the coefficient also suggests that the interaction between 

Batches HL3 and HL6 met the set criteria of 

, < 25%. Batches HL3, HL5, HL6, and HL9 met the set criteria of 

 < 60%. Batches HL6 and HL9 met the set criteria of 

  between 490 and 590 min. Among the entire batches, only HL6 fulfilled all the selection criteria, which included prolonged drug release of the remaining drug over 12 h. Batch HL6, therefore, was selected as the optimized batch. 

The dissolution data of batch HL6 were compared with the ideal release profile using f

value of 87.86 indicates that the release profile of batch HL6 was comparable with the ideal batch. A value of f

 ≥ 50 is necessary for similarity in dissolution profile at 10% difference. Table V shows the results of multiple linear regression for the response 

  indicate good fit. The drug release of the best batch HL6 was also conducted in phosphate buffer (pH 6.8). The dissolution data of batch HL6 in distilled water were compared with the dissolution data in phosphate buffer (pH 6.8). An f

 of 89.68 indicated that the release profile of batch HL6 in distilled water and phosphate buffer were comparable. Lastly, the dissolution of batch HL6 was compared with the market preparation of the drug in distilled water. The dissolution data of both were compared using f

 of 90.48 indicates that the release profile of batch HL6 and the market preparation of the drug were comparable. 

Natural gums and mucilage are biocompatible, cheap, readily available, and represent a potential source of excipients. The authors examine the functionality of mucilage extracted from the leaves of Hibiscus rosa-sinensis Linn as an excipient in a sustained-release tablet formulation.

Assessing Hibiscus rosa-sinensis Linn as an Excipient in Sustained-Release Tablets

The authors propose several models for independent evaluation of new excipients.

Clearing Regulatory Hurdles

A global drug master file system may pave the way for faster qualifications of new excipients and the industry's acceptance of their use in drug therapies.