Enhancing the solubility of poorly water soluble drugs

Review article: Gunjan Subedi, Kathmandu University

Click here to view the review article of Mr. Gunjan Subedi

on Enhancing the solubility of poorly water soluble drugs.

Abstract :

Each drug molecule have own inherent material properties (physical\chemical) such as solubility which varies from one to another. As more than one third of drug molecule of US Pharmacopoeia are listed under class of poorly soluble or insoluble, conversion of such drug candidate ( poor soluble or insoluble) always makes challenge to formulate and develop dosage form with better bioavailability where solubility act as key determinant for absorption. A researcher's ultimate objective is to maximize the solubility characteristics of such molecule. In order to achieve such objectives we have to modify their inherent physical as well chemical properties (without altering therapeutic value) by applying any of the above discussed physical/ chemical/other techniques based on their material properties. The approaches described here are of great help in enhancing the solubility of poorly soluble drug molecules shows great promise for development of dosage forms using such APIs.

FUTURE OF PHARMACY

Pharmacy can be defined as a field related to drugs and practices that involves all the areas related to knowledge building, research, discovery, rational use, business, treatment and safety of drugs". Its definition extends right from the time when people feel the need of molecule to treat a specific disease and lead compounds are researched in the labs to the time when post marketing surveillance for the feedback of drug is gathered.

I see that the future is going much closer to the targeted drug delivery than the traditional formulations. With the development of the genome science, gene drug delivery systems, nanotechnology, liposomes, etc we are moving in a age where we are concerned for developing a drug that targets only for the area of the body where there is a harm by disease rather than the conventional system where drug gets distributed all over the body through blood circulation.

Where is the future of pharmacy involved in discovery and development going? The full cost of bringing a new drug (i.e. a drug that is a new chemical entity) to market (from discovery through clinical trials to approval) is complex and controversial. 2012 data on a forbes magazine shows the average cost of bringing a new drug to market is $1.3 billion. So rather than investing on the R & D of new molecules companies now  prefer optimizing the existing molecules and enhancing the efficiency of the already developed drugs. There is an increase in immense interest in developing new drug delivery systems. When I surfed across various informative journals in internet, I found that for cancer, the 5 year survival rates in 1970 was 49%. And in 2007, the survival rate was 67%. Now, its 74%. Thanks to the nanoformulation targeted drug delivery systems which have still greater potential for many applications, including anti-tumour therapy, gene therapy, AIDS therapy, radiotherapy in the delivery of proteins, antibiotics, virostatics, vaccines and as vesicles to pass the blood-brain barrier. Cardiovascular disease fall almost 30% between 1997 and 2007 in large part due to improved treatment options and Gene mapping technology is spurring the no. of new innovations, technoloies and stratigies to diagnose and treat disease. The introduction of HAART (highly active retroviral therapy) has turned HIV/AIDS from a deadly disease into one with good long-term survival , (the death rate in US has fallen by 83% since 1995.

Where is the future pharma economics and pharma patenting heading ? When I first joined the pharmaceutical industry, some years back, there were many US based companies having the patent rights. In 2011 and 2012 alone about some of the biggest blockbuster drugs in history lost patent protection. Drugs like Lipitor, Plavix and Viagra which earned billions for their sponsors and which  are generating $133 billions in US will now be facing great competitors. Pharmaceutical companies are now more interested in Biopharmaceutical innovation. Biopharmaceutical products such as insulin, protein, supplements have generated a comparable revenue as pharmaceutical products in revent years. More patents are being generated for biopharmaceutical products and development of drug delivery patents. Most of these are related to nanotechnology and targeted controlled drug delivery systems.

Where is the future community, hospital and clinical pharmacy heading? With the inclusion of many drugs in the OTC list and law enforced by governmental bodies of most of the countries, Pharmacy will soon become an inevitable profession in most of the hospitals, clinics and community settings. Pharmacists will be the main authoritative bodies in dispensing, councelling and prescribing of many drugs. Pharmacists will have a key role to play in planning and implementation in health research and issues in community level too.

Where are the future Pharma Academia heading? Future Academia will be more focused in research than the taught courses. Large drug research and developing companies feel too risky and lengthy to carry out all the activities on their own now so they are collaborating with different universities for research. Doing so will generate new ideas among the students and helps them to learn and it also minimizes the time, effort and money for the big companies  in the discovery of molecules and optimizing the lead compounds and drug delivery system. Research based universities basically in Korea, Australia, Netherlands, U.S.etc.  are basically carrying out a huge proportion of research works in collaboration with the pharmaceutical industries. 

Pharmacy has a great future and potential to improve the health and income status of many countries. There will soon come a future that through genomic study, the fate of disease and life of a man will be discovered before his birth. There will soon come a future that man gets his disease cured by altering his genomic patterns. However, we must not forget that there are still corners in this world that for a single dose of pill , a patient has to walk on sloppy hills for days. There are still millions of people who die of many preventable simple diseases like diarrhea, dysentery cholera and typhoid. I remember a time when I was volunteering  in a free health camp in remote village in Jajarkot, Nepal where I was left empty of Zinc tablets and children were dying before my eyesight. 
 

I genuinely feel- THE FUTURE OF PHARMACY SHOULD BE ORIENTED TOWARDS HUMANE EFFORTS TO MITIGATE THE PAINS OF THE NEEDY. KNOWLEDGE AND TECHNOLOGY CANNOT MASTER THE PAIN UNLESS IT REACHES THE UNDERPRIVELEDGED ONES.

In vitro evaluation of a fast-disintegrating lyophilized dry emulsion tablet containing griseofulvin and comparison with its conventional dosage form

In vitro evaluation of a fast-disintegrating lyophilized dry emulsion tablet containing griseofulvin and comparison with its conventional dosage form

Rationale
Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption). The dry emulsion can be formed from following possible ways:
• Freeze drying/ Lyophilization
• Spray Drying
• Solvent evaporation by vaccum drying

We choosed griseofulvin for our project. According to the biopharmaceutical classification system (BCS), to Class II of drugs with poor solubility and high permeability for doses of 125 and 250mg. Class II drugs usually suffer from low bioavailability following oral administration of traditional dosage forms. The purpose of this study was to investigate the in vitro dissolution of GF from lyophilized dry o/w emulsion (LDE) tablets. LDE tablets could be useful for the delivery of poorly soluble drugs for which fat co-administration results in improving bioavailability or for which an increased oral bioavailability is observed when incorporated in o/w emulsions. Freeze-dried emulsion tablets have the advantage of sharing the properties of freeze-dried dosage forms, such as rapid reconstitution, good preservation, and stability. The tablets also disintegrate rapidly in the mouth upon contact with saliva and therefore do not need to be swallowed, which usually results in improving patient’s compliance and acceptability.




Materials and Method.
All chemicals used will be of analytical grade.
Emulsion(%,w/w) Tablet theoretical composition (mg;w/w)
F1
Gelatin (2%, w/v) 78.3 Gelatin 18
HPMC 2.2 HPMC 25.3
Miglyol 8.7 Miglyol 100
GF 10.8 GF 125
F2
Gelatin (2%, w/v) 78.3 Gelatin 18
HPMC 2.2 HPMC 25.3
Sesame oil 8.7 Sesame oil 100
GF 10.8 GF 125
F3
Gelatin (2%, w/v) 76.6 Gelatin 18
Tween 80/ Span 80 4.25 Tween 80/ Span 80 50
Miglyol 8.5 Miglyol 100
GF 10.6 GF 125
F4
Gelatin (2%, w/v) 77.2 Gelatin 18
HPMC 2.1 HPMC 24.5
Sorbitol 0.7 Sorbitol 8.16
Glycine 0.7 Glycine 8.16
Miglyol 8.6 Miglyol 100.3
GF 10.72 GF 125
F5
Gelatin (2%, w/v) 75.6 Gelatin 18
HPMC 4.2 HPMC 50
Sorbitol 0.67 Sorbitol 7.9
Glycine 0.67 Glycine 7.9
Miglyol 8.4 Miglyol 100
GF 10.5 GF 125

Method
This technology includes physical trapping of the drug in the matrix composed of a saccharide and a polymer. Polymers generally employed are partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginates, polyvinyl pyrrolidine, acacia, and these mixtures.
The methodology involves solution or dispersion of components is prepared and filled into blister cavities which are frozen below their eutectic point or below their glass trasition temperature. The frozen mixture is heated at low pressure called vaccum drying, above its collapse temperature causing water to sublimate and produce highly porous tablets. This idea come to first patented as zydis technology which was the first of its kind. This process is performed in Lyophilization equipment which consists of a drying chamber with temperature controlled shelves, a condenser to trap water removed from the product, a cooling system to supply refrigerant to the shelves and the condenser, and a vaccum system to reduce the pressure in the chamber and condenser to facilitate the drying process.

References

1. Iman Saad Ahmed, Mona Hassan Aboul-Einien, In vitro and in vivo evaluation of a fast-disintegrating lyophilized dry emulsion tablet containing griseofulvin, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr-El-Eini St., Cairo, Egypt
2. http://www.wikipedia/griseofulvin.org
3. Aulton.M.E., Dosage Form Design and Manufacture. Pharmaceutics: The Science of Dosage Form Design, 2nd Edition, 2002 :( 307-339)
4. www.elsevier.com/locate/ejps
5. www.hinary.org

FORMULATION AND IN-VITRO EVALUATION OF RABEPRAZOLE FAST RELEASE TABLETS...an initiative of Senior Phr. Sashikt Chaudhary and project thesis

1. Rationale of the Project:

Several approaches on the preparation of the fast release tablet dosage form has been done in the past. A fast release dosage form releases in the stomach in less than 30 minutes. The theme behind this project is to form a fast release tablet dosage form by using the buffer system. The advantages outstand when rabeprazole is used along with the buffering agents such as sodium bicarbonate and calcium carbonate(2). The buffered system rapidly disintegrates within the aqueous stomach media even if the stomach has minimal motility. Another benefit is that these buffers protect rabeprazole from the degradation of Rabeprazol by HCl in stomach. We can decrease the onset of action to 30 minutes compared to other PPIs (1-2hrs) with the buffered system(2).Due to the acid neutralizing property of the buffer itself, a fast symptomatic relief (60 seconds) can be acquired. The buffered system of Rabeprazole helps to hasten the onset of action over the other enteric coated formulation as it has early Tmax(3.5 hrs).(3) It has the activation half life of 7.2 min which leads to faster PH control and symptom relief as compared to other PPI's
Approaches for fast release of drug formulation:

i. Modification of the drug's lipophilicity such as by esterification of the drug.(1)
ii. Altering the permeability of the gastrointestinal cell membranes by the use of absorption enhancers.(1)
iii. Creating alkaline pH in gastric environment which facilitates the absorption of drug in stomach.(4)
iv. Increasing the solubility of the drug by using the salt form of the drug or incorporating into the formulation a substance that forms a salt with the drug during dissolution.( eg. increase the dissolution of aspirin by using the magnesium oxide in the formulation) (1)
v. Use of the buffered systems and enteric aqueous coating formulations (2)/(3)

2. Rabeprazole-Drug Profile:
Rabeprazole is a Proton-Pump Inhibitor which works by decreasing the secretion of the acid in the stomach by the inhibition of (H/K)-ATPase. It is a substituted benzimidazole used for decreasing gastric acid secretion.(9). It is used to treat ulcers, gastroesophageal reflux disease (GERD), heartburn and Zollinger-Ellison syndrome. Rabeprazole is used in combination with medications like amoxicillin and clarithromycin to eliminate H. pylori, a bacterium that causes ulcers(5)/(7). Rabeprazole used alone is better than any other PPIs for eg, its bioavailability is 52% time dependent and has 10000 folds of acid trapping property compared to that of omeprazole which has only 1000 folds of acid trapping property and 64% time dependent bioavailability(2) .Its high pKa value(4.9) offer the advantage of its 10 times more accumulation compared to other PPIs (eg Omeprazole having pKa of 4.3) in the gastric parietal cell's canaliculi. Rabeprazole inhibits the basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (9). It is only the PPI known to increase the mucous formation. The property of rabeprazole in increasing the formation of the mucous helps in making a barrier between the acid and the underlying tissues. It has no side effects related to gastro intestinal hormones.



3. Aims: The aim of this project is to formulate Rabeprazole fast release in tablet dosage form, to optimize the drug release profile and evaluate its in-vitro analysis variables.
4. Objectives:
1. To design an Rabeprazole fast release tablets using Sodium bicarbonate and magnesium Oxide etc.
2. To compare the drug release and the release rates from the market product with that of different formulations prepared.
3. To perform in-vitro analysis on drug release rate from the formulated tablets.

4. Ho: There is no difference in the mechanism and rate of drug release from the leading market product with that of different formulations formulated.
5. HA: There is difference in the mechanism and rate of drug release from the market product with that of different formulations formulated.
5. Materials and Machines Required:
5.1 Raw materials:
a) Active Pharmaceutical Ingredients – Rabeprazole sodium,
b) Binder – Hydroxypropyl Cellulose, Low Substituted Hydroxypropyl Cellulose( L-HPC, L-21 )
c) Buffering agents : (Sodium Bicarbonate, Magnesium Oxide and Calcium carbonate)
d) Diluents- Powder Mannitol, Magnesium Oxide,
e) Disintegrant : Low Substituted Hydroxypropyl Cellulose( L-HPC, L-21 ), Croscarmellose Sodium, Sodium Starch Glycollate.
f) Lubricants (P. Talc, Magnesium Stearate)
g) Polymers: Hydroxypropyl
h) Solvents- Methylene chloride, Isopropyl alcohol, Water.
5.2 Reagents:
a) Depends upon analytical procedure developed.
5.3 Equipments and Instruments:
a) Analytical and precision balance
b) Lab model mass mixer
c) Shifter
d) Tray drier/ Fluid Bed Drier
e) IR moisture balance
f) Dehumidifier
g) Tablet compression machine
h) Friability tester
i) Hardness tester
j) Disintegration Test apparatus
k) Dissolution test apparatus
l) UV-Visible spectrophotometer/ HPLC- depend upon analytical procedure.

6. Methodology:
First we take mannitol and crospovidone along with the buffering agents calcium carbonate and sodium bicarbonate, magnesium oxide, low-substituted hydroxypropylcellulose, and magnesium stearate and mix with rabeprazole sodium as a core formulation and follow the wet granulation. The granules are then dried using a fluidised bed drier and then passed through a 1.5 mm screen. Dried granules are blended with the rest of L-HPC and magnesium stearate in a V-blender. Density of the final granulation is then measured with a tapped density tester. The powder mass is then compressed using a compression machine. The uncoated tablets is then subjected to a film coating using a solution ethylcellulose/magnesium oxide(1:1%w/w) dispersion and then with aqueous enteric coating with Acryl EZE which is a aqueous enteric coating based on methacrylic acid copolymer type C. The tablets are then tested for the acid uptake value and the dissolution test is run and the drug release is tested using the HPLC analysis. Then, the release pattern and the dissolution profile our buffered system formulation is compared with the enteric coated conventional marketed products.
6.1 Research design:
• The batches of tablets with minimum batch size of 100 tablets will be taken using the Buffering agent at different concentration.
• The release profile of the first batch will be studied and from its result, subsequent batches will be designed to get the desired characters.
• Tablet compression will be done and their variability will be studied.
6.2 Research Laboratory:
• All the work will be conducted in Qmed Formulation Pvt. Ltd., Chhaling-5, Bhaktapur, Nepal.
6.3 Materials Required and Cost of the Project:
• The Qmed Formulation Pvt. Ltd. has agreed to provide the materials and equipments that are available in the company.
• Other material if required has to be purchased.
• The estimated cost of the project is around 18000/- ( Eighteen thousand only)

7. Conclusion In this project a new method of enhancing the release profile of the drug, improving the dissolution and decreasing the time of onset of action will be studied. The effects of various concentration of the buffering agents, drug release patents, extent and rate of release will be studied. A validated method for the development of fast release formulation will thus be developed. The formulation will then be compared with the marketed product and the dummy and the conclusion will then be made on the basis of the observation and the data obtained.

References:
1. Aulton Michael E., Aulton's Pharmaceutics The design and Manufacture of Medicines, Third edition, Churchill Livingstone Elsevier Publication, Pg. 455-456

2. Application of a Fully Formulated Aqueous Enteric Coating System on Rabeprazole Sodium Tablets (20 mg)

3. Enteric coated Rabeprazole Sodium and Itopride Hydrochloride sustained
release capsules

4. www.patentdocs.com

5. www.wikipedia/rabeprazole

6. http://www.who.int/medicines

7. http://www.medpedia/rabeprazole

8. The selection and use of essential medicines, WHO Technical Report series, 2009
9. http://www.colorcon/acryl-EZE

10. Raymond C. etal, "Handbook of Pharmaceutical excipients",PhP Pharmaceutical Press, London, ChicagoRaymond C Rowe, Paul J

NATUROPATHY AND NEPALESE MARKET

Naturopathy is a clinical specialty that emphasizes the use of natural products in both prevention and treatment of disease. It is founded on six basic principles:


1. Nature has the power to heal
2. Treat the whole person
3. Do not harm
4. Identify and treat the cause of the disease
5. Prevention is as important as cure
6. Doctors should be teachers

Naturopathic doctors use many forms of therapy including therapeutic diets, fasting, herbal supplements, hydrotherapy, psychotherapy, stress management, massage and other physical manipulation therapies, and homeopathy. In some place they can perform minor surgeries and prescribe specific conventional medicines such as antibiotics.

Naturopathy appears to be effective in treating the following:

• asthma
• osteoarthritis
• cardiovascular disease (CHD)
• hypertension
• benign prostatic hypertrophy
• diabetes mellitus
• irritable bowel syndrome (IBS)
• premenstrual syndrome (PMS)
• vaginitis
• eczema

It is also effective for other chronic and acute conditions, and in promoting weight loss.

There are very few rigorous, placebo-controlled, clinical trials (RCTs) of naturopathy, and therefore the scientific basis for the clinical efficacy of naturopathy is weak..

Given this lack of general research in naturopathy and the fact that scientific journals generally publish fewer “negative outcome” studies (in which the intervention does not work), there is a virtual absence of any scientific documentation and research of what does not work in naturopathic medicine.

ARE HERBAL MEDICAL REMEDIES SAFE? TAKE THE SCENERIO OF NEPAL AND THE WORLD?

NO.
Even if a doctor or a prescriber proclaims of safety of the Herbal medicines totally, They are not safe if used unproperly and without planning.

Reasons-

1. Certain plants and plants derived products are toxic.
2. Herb industry is very unregulated not only in Nepal but also worldwide.
3. There is no formal practice of herbal medicines in Medical students and pharmacists so that potential side effects and interactions when used along with the allopathic treatment is By-passed.

4. As long as the herb industry remains unregulated, manufacturers have no reason to establish quality controls insuring that each batch of medicine contains the same amount of active ingredient. And without quality control, many herbs and supplements will carry inadequate or inaccurate labeling.

5. All herbal dosages and recommendations are based on studies with adults, and the safety and efficacy of these products for children is completely unknown. Adults over age 65 may have diminished liver or kidney function and need to be particularly concerned about excess dosages and the toxic effects of herbal remedies or supplements

6. How herbal preparations interact with foods is another unknown question.

WHY AND WHY NOT TO SWITCH ON HERBS AND HERBAL MEDICINE? SHOULD NEPAL NOW FOCUS ON HERBAL MEDICINES?

Herbal remedies have been used for thousands of years. Today an estimated one-third of adult Americans—some 60 million people—use herbal medicines each year, spending more than $3.2 billion on them. In the rest of the world, approximately 64 percent of the population relies on herbal medicines. Despite their overwhelming popularity and long history, we know relatively little about the safety and effectiveness of herbal remedies. Scientific study should make these remedies far safer and more effective in the future. Global recognition of nature’s green pharmacy should inspire individuals and nations to protect this extraordinary resource.

What is the real world scenario of Drug Development? How are the modern Drugs related to the Prehistoric Herbs and treatment Process?

Modern pharmaceuticals cannot treat every condition effectively, and some drugs have unwanted side effects. In the late 20th century herbal medicine made a comeback as people began to seek alternatives to these drugs.

Just forgetting the Nepalese and the world market let us just concentrate in the U.S. Scenerio. Today more than 1,500 herbal preparations are marketed in the United States, not only in health food stores but also in pharmacies, supermarkets, department stores, and even truck stops.
Another indication of the importance of herbals: About one-quarter of all U.S. prescription drugs are derived from herbs. The pharmaceutical industry uses around 120 different compounds derived from plants in the drugs it manufactures, and it discovered nearly three-quarters of these compounds by studying folk remedies. Examples of drugs from plants include quinine, from the bark of the South American cinchona tree, used to treat some strains of malaria; digitalis, a widely prescribed heart medication, derived from the foxglove plant; salicylic acid, the source of aspirin, from willow bark; and taxol, for treating ovarian cancer, from the yew tree.