Luigi G. Martini

The pharmaceutical landscape is changing. For the last four decades the pharmaceutical industry has focused its attentions on servicing the needs of the western and developed markets with very little attention paid to what used to be referred to as 'the international markets'. However, with advances in science, medicine and technology, many new 'pharmerging' markets are being created with rapid phases of growth and expansion. For example, the emerging markets of Brazil, Russia, India, Turkey, Mexico, South Korea and China will soon account for around 50% of the global pharmaceutical growth by end of 2010.

The importance of the emerging markets becomes apparent when one considers that diseases that were once prominent in the West and scarce in the East are now becoming prevalent in countries such as China as their economies grow and their citizens adopt western lifestyles.     

This article discusses the importance of developing medicinal products for the emerging markets and the various factors that need to be considered, using China as the primary example. 

Serving unmet and growing medical need: a focus on China

  conducted in China have shown the following diseases to be widespread: HIV, hepatitis, cardiovascular and cancers. 

 shows how China is catching up with the US with respect to the main causes of death from illness and disease. 

The United Nations investigated the prevalence of AIDS in China in 2008

  and found that 700 000 people were living with HIV, with 75 000 of these cases having developed into full-blown AIDS. The Chinese Government is therefore naturally concerned by the threat of HIV to the rest of the population. 

There are two forms of hepatitis (inflammatory liver disease) — B and C. It has been estimated that there are 170 million people infected with hepatitis B in China. This patient population is poorly served; a mere 4% of sufferers receive treatment and, as a result, 300 000 people in China die each year from the disease. 

Hepatitis C, which is a more virulent form of the virus, currently affects 46 million people in China. This number dwarfs the incidence of the disease in the US, UK, Spain, Japan, Germany and France combined. 

According to a study by Arnold and co-workers,

  there are approximately 40 million diabetics in China with around 1.5 million new cases reported each year. Studies show that the prevalence of diabetes is stratified across China as follows: 2% in rural towns, 4% in small cities, and 6% in large cities (Beijing and Shanghai account for up to 10% of this figure).  

China has a high incidence of lung, mouth and neck cancers predominantly influenced by the high levels of smoking in the country. The WHO estimates that cancer is one of the main causes of death in China with an incidence level of 13% and this is projected to rise to 24% by 2030.

Does serving unmet medical need in the emerging markets make good business sense?

Emerging markets are usually defined as those markets or regions that are expected to experience high economic growth and, if we use this definition then it certainly does make good business sense to serve unmet medical need in these markets. According to Pacek and Thorniley

 : "Countries such as China, Russia, India, Brazil and Turkey will be the engines of corporate growth. By 2015, China and India will account for 25% of the world output in real terms and by 2025, 50% of world exports will come from emerging market economies compared with only 10% in 1980 and 25% in 2004." 

 depicts Gross Domestic Product (GDP) for a number of western markets compared with Brazil, Russia, India and China (BRIC) markets.  

From the data, it appears evident that all the emerging markets are on course to outperform the developed markets of the US and the Euro Zone. According to recent data, the economic potential for China is further enhanced by its low debt levels to GDP ratio.

  It is not surprising, therefore, that many corporations have actively pursued sales in these regions; many CEOs have expressed their desire to expand their position in China. For example, Andrew Witty, CEO of GlaxoSmithKline (GSK) Pharmaceuticals, gave the following quote: 

"I've lived in Africa, I've lived in Asia. I've spent a lot of my career outside Britain and a big chunk of it in the emerging world and I think there's tremendous scope for companies like GSK to play a very constructive role.'' (Sunday Telegraph, 7 February 2010) 

Meanwhile, Pfizer, the world's largest pharmaceutical company, is apparently aiming to add $3 billion sales in the emerging markets by 2012.

  Of particular interest to Pfizer are the markets of China, Brazil, Mexico, Russia, India and Turkey. The President of emerging markets at Pfizer, Jean-Michel Halfon, told Reuters

 "The emerging markets pie could increase to $120 billion by 2012 with China providing the greatest growth prospects". 

 It is also not surprising that China is the major market and prize in waiting. 

  and projected through to 2013 has shown the following:  

 Current sales of pharmaceuticals in China exceed £15 billion.  

China is currently the sixth largest pharma market in the world and is forecast to be the third largest by 2013. 

The growth rate of the Chinese pharma market is predicted to be around 20% (CAGR) through 2013. 

In addition, what makes China equally attractive are the following demographics,

  which make the healthcare sector worthy of pursuit:  

 Massive consumer base: China has the second largest birth cohort in the world (16 million births/year. Compare this with the population size of Australia at 19 million).  

Aging population: by 2015 140 million people will hit the 50+ age segment in China, leading to higher demand for medical treatment. 

Urbanisation: by 2015, 160 million will migrate towards urban China. 

Healthcare reform: the Chinese government aims to make healthcare available to more than 90% of the urban and rural residents by 2011.   

However there are a number of challenges for western pharmaceutical companies developing products in China:  

 Slow and conservative regulatory process for approval of new drug products. 

Pricing of drug products is complicated and open to interpretation. 

Counterfeit medicines are a real concern. 

High levels of capital investment are required to penetrate and maintain a credible presence in China. 

However, from my own experiences of running projects in China, it is evident that widespread changes have occurred, heralding a safer and more patient centric welfare state. 

As Government reforms begin to take shape in China, it is anticipated that healthcare provision will begin to spread outwards from Tier 1 into Tier 2 and Tier 3 cities. A Tier 1 city has a registered population >4.5 million and a GDP/Capita >US$3000 e.g., Shanghai, Beijing, Guangzhou and Shenzhen. A Tier 2 city is defined as having either >4.5 million or GDP/Capita >US$3000 e.g., Tianjin and Chongqing. Meanwhile, a Tier 3 city is defined as having a population of 1.5–4.5 million and GDP/Capita in the range US$1500–$3000. 

To put it into context; Shanghai (China) is classed as Tier 1 city with a population size of 18 million, whilst other cities outside of China, for example, London (UK) and New York (USA), are also Tier 1 cities but with a population circa 8 million.  

Scaling the pyramid of wealth in the emerging markets and China 

Affordability is key for the emerging markets as the disparity in income levels is particularly heterogeneous in these territories. Although the work by Prahalad and Lieberthal

  is somewhat dated, the general trends that have been summarised in 

 still apply today, in that there are consumers who "Have a lot, Have, Have Less and Have Not".  

Many pharmaceutical companies have traditionally focused on the "Have a Lot" segment and have very limited experience in developing low cost medicines or supplying generic drugs. However, a high proportion of the Chinese population resides in the 'Have Less than $5000' bracket (typically young professionals, graduates and people who run their own businesses). In contrast to the traditional approach, GSK is proposing a portfolio of offerings (see 

) in order to compete with the cost leadership position that many generic companies have already established in China.

Sidebar: GSK approach to sustaining R&D in the emerging markets 

Articles

The emerging markets represent an attractive investment opportunity for the pharmaceutical industry because of the countries' growing economies and unmet medical needs.

Do emerging markets provide the answer to the pharmaceutical industry?

Oral absorption efficiency can be influenced by several factors, acting independently or in concert. These include the physicochemical properties of the administered agent, human physiology, pathology (including disease state), the way the drug is presented (formulated) and possibly the amount that is administered (dose). Other influences include time of administration, whether the patient is resting or active and body position, for example, recumbent or standing. Optimizing absorption requires knowledge of how these variables affect the drug or formulation. However, it may take many years before such comprehensive knowledge can be gleaned on compound-specific behaviours. 

In the absence of such detailed insight it may necessary, particularly with novel therapeutic agents being dosed to humans for the first time, to design a formulation based on generic considerations of factors affecting absorption, the physicochemical properties of the agent being administered and 

 findings in animals or animal tissue. Such a strategy can help identify the optimum form of the drug and clarify possibilities and limitations for manipulating its properties to optimize delivery.  

Hence, good understanding of the physicochemical properties of the drug, and of the anatomy and physiology of the gastrointestinal (GI) tract provides valuable insight on the possibilities and constraints for optimizing oral absorption. 			

Some materials are absorbed by active transport across the intestinal barrier, but absorption by passive diffusion is probably far more prevalent.

  Regardless of the mode of transport, however, it is reasonable to conclude that, in the vast majority of cases the drug must be in the solvated state to diffuse into and across the enterocytes lining the intestinal lumen. Thus, solubility and rate of dissolution of the drug are of major importance and many approaches to absorption enhancement concern the optimization of these properties. 

Table I Aqueous solubilities of tetracycline and erythromycin derivatives. 			

Poorly soluble drugs present a major challenge in dosage form development. In simple terms, a material must be in solution if it is to pass from the intestine to the systemic system. At the same time, lipophilicity is frequently associated with higher activity, or receptor specificity and is invariably incorporated in molecular structures by the medicinal chemist. Low aqueous solubility (which is usually associated with high lipophilicity) and poor bioavailability are often a consequence of such molecular design. Improving absorption in such cases may mean using a form of the drug with optimum solubility, or employing a vehicle in which the compound is soluble. Optimizing solubility may entail using a more soluble salt or polymorph (if one exists), or even the amorphous form of a compound. Each approach has advantages and complications, and such options may not always be available, depending on the molecular composition and physical behaviours of the material under consideration. 			

 Agharkar found that the solubility of the free base form of the antimalarial, Î±-(2-piperidyl)-Î²-3, 6-bis(trifluoromethyl)-9-phenanthrenemethanol was 7 Î¼g/mL.

  The hydrochloride salt in contrast had solubility of approximately 30 Î¼g/mL whereas a value of 1800 Î¼g/mL was attained for the dl-lactate salt. Tetracycline and erythromycin salts also exhibit differing solubilities (Table I). Bastin 

 also found that some salts of the cardiovascular compound RPR127963 afforded significantly improved solubilites compared with the free base (Table II).

Enhanced solubility does not necessarily translate to better 

 absorption. There are several reports of salts with differing solubilities behaving no differently in bioavailability studies.

  Better solubility may simply be a pH effect that is neutralized in the gastric or intestinal milieu, with solubility changing to reflect local environmental pH. Conversely, it is also feasible that the pH engendered by a salt in its micro-environment facilitates dissolution. The salt acts as its own buffer so to speak. Once in the solvated state, the dynamics of transport or reprecipitation may be such that there is a net enhancement of amount dissolved and absorbed. 

Table II Aqueous solubilities of salts of RPR127963.			

The counter ion can be important for other reasons. Many drug substances are organic bases, and hydrochlorides are usually the first (sometimes only) salts considered when seeking a more soluble form. However, the presence of chloride ions in gastric acid may well depress solubility 

  Consequently, absorption may not be improved.  

  The hydrochloride and mesylate salts of two novel protein kinase inhibitors were more soluble than other salts, but when bioavailability in beagle dogs was evaluated the mesylate salts of both compounds had better bioavailabilities than the hydrochlorides (Figure 1). 			

This may have been because of better solubility of the mesylate salts (five times more soluble than hydrochloride), but a common ion effect with the hydrochloride salts cannot be ruled out. Interestingly, these authors established (from a review of recently approved compounds) that mesylate salts are now being more widely used. It would be of interest if such increasing popularity was a result of better 

Table III Bioavailability of tolbutamide polymorphs in dogs.*

The potential for absorption enhancement by salts could be usefully explored in small animal 

 studies, particularly in cases where human studies are not possible or appropriate; for example, at the compound selection stage in drug discovery programmes. Animal studies, while not necessarily predicting absorption efficiency in humans may provide useful rank order ratings on the effects of different salts. 			

 Medicinal compounds may exist in a variety of crystal forms that can have differing aqueous solubilities. Riboflavin has three polymorphs with solubilities varying from 0.06-1.2 mg/mL

  Bioavailability of various morphic forms of cimetidine was shown to correlate with dissolution rates suggesting that solubility might be important for oral absorption.

 obtained differing plasma levels in dogs when dosed with different polymorphs of the poorly soluble hypoglycaemic agent tolbutamide (Table III).

 differences in dissolution rates and solubilities between the forms. 			

Polymorphs with the lowest free energy (lowest solubility) are usually most stable in thermodynamic terms; more soluble forms tend to transform to the low energy state. Such transformation can occur during storage, processing or even during dissolution.

  This makes polymorph selection for solubility enhancement an uncertain process. The more soluble form might become less soluble with time because of reversion to the more thermodynamically stable form, with absorption being compromised as a consequence. It is important, therefore, that any promising crystal form is thoroughly assessed to confirm that: 					

It can be prepared consistently by a realistic and reliable process.

The preferred form can be readily identified by a technique suitable for routine quality control.

It does not transform to a less useful form on storage, during processing or after incorporation in the dosage form.

It does not transform to the less soluble state after ingestion but prior to absorption; that is, in the GI tract environment. 

Figure 1 Mean plasma concentrations of LY333531 and LY338522 in male beagle dogs orally administered with LY333531ÃÂ·HCl and LY333531 mesylate (20 mg LY333531/kg).*						

Modest improvements in solubility or dissolution rate may be of little benefit 

 claimed that slight differences in solubility and dissolution rate of the anhydrous and trihydrate forms of the antibacterial ampicillin lead to differences in oral bioavailability in dogs and humans.

  However, a later study using unformulated drug showed that both forms were bioequivalent, suggesting that the results from the Poole study might be ascribable to formulation differences.

  The work by Aguiar and Zelmer provides further elucidation on solubility differences. They showed, using polymorphs of mefenamic acid and chloramphenicol, that when free energy differences (reflecting solubility values across a range of temperatures) were modest, bioavailability differences would not be expected. When differences are large they can affect absorption.

Amorphous materials can be more soluble and have faster dissolution rates than crystalline forms because of lower solvation energy. Amorphous novobiocin dissolves rapidly and is well absorbed in humans. The crystalline form, by contrast, is less soluble, has slower dissolution rates, and exhibits poor and erratic bioavailability.

Amorphous materials have the same potential disadvantages as polymorphs or pseudopolymorphs in that they may transform to the less soluble crystalline state. The molecular mobility (and associated tendency to transform) of an a morphous solid is a function of the differential between storage temperature and its glass transition temperature (T

). It has been claimed that storage at temperatures of 50 Â°C below T

 for most amorphous solids should be greater than 75-80 Â°C if they are to remain stable in the morphic sense at ambient storage. Excipients with a much higher T

 can sometimes be added to stabilize a drug in the amorphous state. For instance, polyvinylpyrrolidone (PVP) (T

 of 280 Â°C) inhibits the crystallization of  indomethacin.

Table IV Organic solvents used in parenteral formulations.*			

Crystallization is the preferred technique of the organic chemist for isolation in a pure state, and provides a consistent physical form. Isolation may be more difficult if an amorphous form is preferred. "Upstream" purification, or reprecipitation following original isolation in the crystalline state may be necessary. This will add to cost and complexity.  			

Whereas it may be advantageous from an absorption perspective to select a particular salt, polymorph or material in some other physical state, other selection criteria must not be ignored. With respect to counter ions in salts, the potassium ion can be a GI irritant unless the dose is low. Other cations, such as magnesium or calcium, can influence GI tract motility and affect absorption where GI tract residence time is important. However, the dose of counter ions may be too low in most cases to evince undesirable effects.  

Different salts might also contain different residual impurities because of solubility, partitioning or crystallization effects during isolation, or different impurities in the reagent providing the desired counter ion. A preferred salt may not be stable or optimal for processing to product because of moisture sorption, flow or compaction properties, or other such pharmaceutical behaviours. In the examples given in Table II, the sulfate salt was chosen because solubility was adequate and the physical characteristics were better than for the more soluble mesylate salt. The selection of a preferred form has to be a multidisciplinary exercise, ensuring that advantages for one facet of the programme are not negatived by introducing other problems. 

Figure 2 Dissolution profiles of itraconazole forms in 0.1N HCl at 25ÃÂ°C. *			

Use of the crystalline form of a drug can be advantageous from purity, stability and processing perspectives. Thus, methods of retaining crystallinity whilst enhancing solubility and bioavailability may be worth considering. The recent upsurge of interest in cocrystal formation reflects this. Properties such as solubility can be influenced by crystal packing and this in turn can be influenced by the crystalline alignment of drug molecules with structurally complementary structures.  

Hydrogen bond donors can, therefore, be aligned with hydrogen acceptors. In this context it appears that drug molecules with appropriate amide groups can align, in the crystallographic sense, with 1,4-dicarboxylic acids such as citric and tartaric acids, which are suitable materials, from a safety perspective.

  The poorly soluble/poorly bioavailable antifungal itraconazole had comparable dissolution profiles with the amorphous, optimally bioenhanced commercial product when presented in cocrystal forms with the L forms of malic and tartaric acids (Figure 2).

  Such crystal engineering technology is potentially very promising for poorly soluble drugs.  

 If a compound is ionizable it may be possible to increase solubility by adjusting pH. Compounds with pKa/b values between 3-11, namely weak acids and bases, may have solubility enhanced  in this way.

  If a drug is poorly soluble at low pH, it is conceivable that co-administration or coformulation with an acid-neutralizing material provides a gastric environment more conducive to better solubility and dissolution rate. Elevation of gastric pH could also reduce presystemic degradation of acid labile compounds, leaving more available for absorption.

Table V Bioavailability of SCH 56952 (azole antifungal).*

Magnesium and calcium carbonate can be used as compression aids in tablet formulations. It is feasible that their acid-neutralizing effects could be capitalized on to enhance absorption of acid labile compounds or those with poor solubility at normal gastric pH. Some antacids have also been shown to increase the rate of passage from the stomach to the small intestine, consequent to elevating gastric pH.

  This can have theoretical benefit, not only for acid-unstable drugs or acid-insoluble drugs, but also where increased rate of absorption can have therapeutic benefit.  

Such possibilities must be carefully considered, however. Any effect is likely to be related to the amount of material utilized. Inadequate quantities may lead to marginal or no benefit; conversely, excessive amounts might stimulate acid rebound. Physiological effects may also play a part. Magnesium carbonate has laxative properties; by contrast calcium carbonate is a known constipating agent. Such effects on GI tract motility could complicate absorption processes. Antacids may also act as adsorbents, making less drug available for dissolution and adsorption.

Absorption enhancement approaches based on altering pH may be difficult to study preclinically in animal models. Differences in gastric volumes, acidity and physiology are likely to complicate responses. There may be no alternative but to explore possibilities in human Phase I studies.  

The least complex way to present a material to the GI tract for absorption is to administer in solution, thereby removing any dissolution stage. Occasionally, non-aqueous (organic) solvents are used to solubilize drugs for parenteral use. Use in oral products is constrained and complicated by many factors. They may not exert sufficient solubilizing action to be of practical value unless the dose of drug is low. Otherwise the volume of vehicle required cannot be readily contained in a convenient dose unit. Liquid-filled gelatin capsules offer possibilities for compounds when the drug dose is approximately 40-60 mg, but only a limited number of non-aqueous solvents can be employed for such presentations.  

Some synthetic aluminosilicates or silicates can absorb significant amounts (up to and exceeding an equal mass) of certain organic solvents whilst retaining the properties of a solid. Drug dissolved in the organic solvent and then absorbed on the silica provides a form that can be filled into capsules and even compressed to tablets.

  The drug is thus "in solution," but can be formulated as a solid dosage form. This approach requires that the drug has high solubility (and good stability) in the chosen organic solvent, and that the silicate in turn has high absorption capability for the solvent. These requirements restrict the applicability to potent medicinal agents (dose not greater than 10-20 mg) that have high solubility suitable of organic solvents. 

Organic solvents can have long-term effects on GI mucosa if the medication is for chronic use, even if levels employed comply with International Conference on Harmonization (ICH) guidelines. It is also possible that precipitation of drug from solution may follow administration, when the material encounters the aqueous environments in the GI tract. Thus, there may be little or no absorption enhancement. Table IV outlines solvents used in commercial parenteral formulations, which with the above caveats might also be considered for oral delivery.

Table VI Pharmacokinetics of unmilled and nanoparticle naproxen in rats.*

Cyclodextrins can provide a novel way to get small-molecule drugs in a molecular dispersion. These cyclic glucose polymers have hydrophilic "outer surfaces" and hydrophobic interior cavities that can accommodate molecules of mass between 400-500 (Figure 3). 

If interactions between drug and the pendant groups within the cavity are strong, a stable molar complex is formed. The compound "hides" in the cavity and the complex assumes the solubility of the cyclodextrin. Dissociation of the complex "releases" the drug in the molecular state.  

Table V summarizes bioavailability data, expressed as "area under curve" (AUC) for an azole antifungal drug dosed to animals, either parenterally or orally, as a hydroxypropyl cyclodextrin complex or as a dispersion in aqueous methylcellulose.

  The cyclodextrin complex afforded better absorption than the conventional suspension in all cases, but the differentials varied with animal species. Data from mice and monkeys suggest that absorption is significantly enhanced whereas improvement was more modest in the dog and rat. Such findings exemplify the uncertainties of accurately predicting absorption in humans using animal models. 

The original (alpha, beta and gamma) cyclodextrins have limited application for solubility enhancement because they themselves are not particularly soluble, thereby limiting the overall dose that can be contained in a conventional unit such as a tablet or capsule. Derivatized cyclodextrins such as the hydroxypropyl or sulfobutyl ether forms are much more soluble. Some have been subjected to comprehensive safety screening and do not seem to have undesirable features such as nephrotoxicity or propensity to cause erythrocyte hemolysis that were associated with earlier cyclodextrins. The sulfobutyl form in particular has excellent solubility; (ca 50 g/100 mL), so can "carry" a lot of drug.

Figure 4 The effects of different solubility and dissolution rate enhancement approaches on absorption.

For a particular cyclodextrin to be suitable for absorption enhancement it must not only accommodate the drug in "molecular dispersion" form to enhance solubility, but must also "release" the drug by complex dissociation in the GI tract. Too stable a complex can be problematical. Trapani showed that when cyclodextrin complexes of the hypnotic zolpidem were dosed to rats the induction period for ataxia was prolonged compared with controls. The effect was ascribed to complex dissociation being rate limiting to absorption.

  Complex formation can, therefore, possibly affect pharmacokinetics and compromise absorption if the complex is too stable. In effect, cyclodextrins, like all other approaches do not always solve solubility-related problems. 

In summary, a number of strategies can be considered for solubility enhancement where this is necessary. The conundrum for the pharmaceutical technologist concerns whether such approaches are warranted. There is fairly general agreement that when aqueous solubility at physiologically relevant pH is less than 1-5 mg/mL at 37 Â°C there is potential for solubility and dissolution-related absorption problems.

  By inference, steps to improve solubility might seem warranted when solubility is lower than this. However, factors such as site-specific absorption, elimination half-life and even dose may also be important. Additionally, it is likely that modest solubility increases may effect little or no improvement, particularly where solubility is very low. Each case must be judged on its merits and studied accordingly.  

This article reviews various physicochemical approaches that may be employed to enhance absorption following oral administration of solid dosage forms in humans. This article also examines strategies based on capitalizing or neutralizing physiological processes.