How the herbal drug-maker uses modern science to unlock the secrets of ancient Ayurveda.

Think herbal drugs and the images that flash through your mind are of a dark-lit, hole-in-the-wall shanty. So, it comes as some surprise when I pull into Himalaya Drug Company's green-and-white building off the Bangalore-Tumkur highway and find, instead of greasy pots and pestles, a modern laboratory buzzing with researchers.

The provocation for my visit is, of course, the January 2003 launch of Himplasia, a herbal drug for benign prostatic hyperplasia (BPH), which is known to affect one of every four men aged 45 or more and almost one in three those above 65. And I've gathered that it's taken Himalaya, a privately-held company, more than eight years of research and development to put the drug on the market. I am curious to find out how drug research and development at a herbal drug manufacturer varies from that of a synthetic drug-maker. And the man who's going to take me through that is Dr Shankar Kumar Mitra (MBBS & MD), Executive Director, Research and Technical Services at Himalaya.

Mitra obviously loves what he does. For, he's all information. Walking around the entrance to the 12-year old facility, he points to a cluster of dark pink flowers. "That's Catharanthus roseus, or Periwinkle. They are the source of two recent alkaloids that are the most potent anti-cancer drugs developed in recent years by international companies," says Mitra. These tiny flowers, he adds, inhibit cancer growth by stopping cell division.

Needless to say, the Rs 300-crore company is also working on the flowers to develop a herbal version of the anti-cancer drug. "It is these unknown or little-known secrets of nature that we are trying to unearth to bring well-researched, effective and safe remedies," says Mitra.

This is where it all begins: Research Head Shankar K. Mitra with Himalaya CEO Ravi Prasad (right) at their Bangalore R&D facility

Unlocking The Secrets
Back at Mitra's office, I am eager to listen to the Himplasia story. I goad Mitra to get into it straight-away. Every drug development at Himalaya, Mitra says, has a typical seven-step process. Since India has the world's richest intellectual capital on herbal medicines, Himalaya's team of 70 researchers begin by studying relevant scientific literature. In this case, it included Charaka Samhita, Sushrata Samhita, and Bhava Prakasha. The idea is to zero down on active ingredients prescribed in these old "medical" journals for enlarged prostate.

Step two (see How Himalaya Developed Himplasia) the team carried out pharmacognosy tests to determine cultivability of the plant(s), and its solubility in water in powder form. Thereafter, experimental trials and toxicity studies are undertaken to ensure the safety and efficacy of the ingredients. Step four involves development of dosage forms and stability studies, to ensure that the drug does not change its characteristics over a period of time.

Much like its synthetic counterpart, the next step for the herbal drug is elaborate clinical trials, comprising four different phases. In phase one, clinical trials are undertaken on healthy volunteers to find out the impact of these drugs. Phase two trials are performed on a limited number of patients who have already been diagnosed as suffering from the disease. In the third phase, multi-centered clinical trials, including random blind testing, is undertaken wherein some patients are given dosages and some placebos to test the efficacy of the medicine. In the fourth and final phase, post-testing surveillance for side-effects is done.

Once the clinical trials are over, the R&D team must ensure standardization through unique TLC (or Thin Layer Chromatography) fingerprinting technique. This technique allows the physical and genetic properties of each ingredient to be tested and measured. Till date, Himalaya has built a genetic bank of more than 500 herbs, the largest database of its kind, claims Mitra. Finally, in year eight, Himplasia is launched.

Ancient scientific literature was researched to ascertain the active ingredients used in products prescribed for prostatic ailments		Tests were undertaken to determine cultivability and solubility of the powdered ingredients in water		Experimental and toxicity studies were undertaken to ensure safety and efficacy of the active ingredients
HOW HIMPLASIA WAS DEVELOPED				Dosage forms were developed, and stability studies conducted to ensure the product does not change characteristics over the long term
Himplasia was launched eight years after work first started on it		Standardization of ingredients was achieved though thin layer chromatography technique		The medicine was put through four stages of clinical trials. All trials adhered to the Helsinki Declaration, which gives primacy to subject safety

The seven steps, however, are neither easy nor fail-proof. The development of Himplasia, for instance, ran into hurdles several times in the eights years. One of the first challenges that the R & D team faced was that BPH patients usually have other associated ailments like hypertension and diabetes. It was important to introduce a product that did not interfere with other treatments. The second challenge lay in the fact that the prevailing treatment required patients to take two medicines. Himalaya wanted a single medicine that had dual action and also acted fast, since many people associate herbal remedies with delayed action.

But does Himplasia score over synthetic equivalents like Minipres XL and Fincar from Pfizer and Cipla, respectively? Philippe J. Haydon, General Manager (Pharma Marketing), Himalaya, thinks so. "The current treatment for BPH has a lot of limitations, including escalating costs." According to Haydon, Himplasia - at Rs. 3 per tablet - is not only cost-effective, but free of side-effects.

Why? Mitra points out that Himplasia has the combination of time-tested herbs, and acts by inhibiting the enzyme (5 alpha reductase) that is responsible for the conversion of testosterone into dihydrotestosterone, which causes prostate enlargement. Besides, it blocks alpha-receptors, another cause of BPH. Therefore, Mitra explains, it helps rectify both irritative (frequent urination) and obstructive (incontinence) symptoms.

Given that few patients with BPH buy drugs over the counter and almost always go with the doctor's prescription, which is usually for synthethic drug, how confident is Himalaya of selling the drug? So confident that it hopes to capture 60 percent of the Rs. 60-crore Indian BPH treatment market in the next one year. Says Ravi Prasad, CEO of Himalaya: "We are trying to educate both the medical community and the end users through leaflets in 10 vernacular languages (apart from English) about both the ailment and how we can help them."

From Serendipity to Science
Commanding credibility is a challenge Himalaya faces with almost each of its products. And its experience has shown that credibility usually comes with time - when the product stays in the market, proves its efficacy, and then is promoted by informal word-of-mouth testimonials. But Prasad admits that the image of Ayurveda and herbal healthcare is far from ideal. "The stereotype herbal manufacturer works in dingy backyards, mixing esoteric herbs that may or may not work. Nothing can be farther from the truth," says Prasad.

Indeed. Himalaya's herbal drugs are developed and manufactured using cutting-edge science, including high performance liquid chromatography meters and thin layer fingerprinting technique. It follows the Helsinki Declaration's norms on clinical research, and its manufacturing facility - can churn out five billion tablets and 60 million bottles a year-is GMP (Good Manufacturing Practice)-certified.

Besides, the therapeutic segments that Himalaya addresses are "modern". These include osteoporosis, diabetes, high blood pressure, menopause, and liver dysfunction, which happens to be its biggest market segment. Every second, a unit of Liv.52 is said to be bought somewhere in the world (that's 3.15 crore units a year). Research firm ORG-MARG puts Liv.52 at number three among all pharma products sold in the country. A reason why last year, Liv.52 fetched Rs. 60 crore for Himalaya.

Seventy-three years ago, when Himalaya was launched, its founder Mr. M. Manal didn't have blockbuster medicines in mind. In fact, his first brush with Ayurveda was the result of serendipity. On a visit to Burma, Manal saw restless elephants being fed a root by their mahouts to pacify them. Intrigued, Manal had the root (Rauwolfia serpentina) scientifically evaluated. After extensive research, he isolated the compound Serpina and launched it as the world's first anti-hypertensive drug in 1934. Some years later, when Ciba independently managed to isolate an alkaloid chemical from the same plant called Resrperine, it became the first allopathic chemical to reduce blood pressure. Although much quicker in effect, Ciba's Resrperine also induced depression in its users, forcing Ciba to recall its early versions. Himalaya's, in contrast, had no side-effects.

Developing a herbal medicine isn't simply a question of plucking a few flowers and herbs and mixing them. Unlike allopathy, where the molecule structure does not vary, there can be huge differences in the properties of the same herb, depending on where it is grown. For instance, Basil (or tulsi) grown in Delhi may not have the same alkaloids as that of the one grown in, say, Chennai.

To control cultivation of its plants and herbs, the company has tied up with several medium and large farmers. Right from identifying the farmer to testing the soil conditions to giving them a final certificate of analysis and buy-back of the produce is done by Himalaya. "Making herbal products is like making Coca-Cola," says Prasad, "The ingredients are known, but unless you also know how to mix them up, you can't produce a copy."

The company has a range of new drugs in the pipleline, especially in the area of oncology (cancer treatment) and personal care products. And R&D, Prasad says, will drive its growth. Not just in India, but in markets abroad, which already contribute 10 per cent of the company's revenues.

As I walk back to my car parked outside the green-and-white R & D facility, I can see the clump of Catharanthus roseus swaying happily in the sun. And something tells me that the men inside the building are smiling too.