University of the Pacific Scholarly Commons University of the Pacific Theses and Graduate School Dissertations 1984 Computerized formulation and optimization of medicated chewing gum Daniel J. Berky University of the Pacific Follow this and additional works at: https://scholarlycommons.edu/uop_etds Part of the Life Sciences Commons, and the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Berky, Daniel J. Computerized formulation and optimization of medicated chewing gum. University of the Pacific, Thesis.edu/uop_etds/473 This Thesis is brought to you for free and open access by the Graduate School at Scholarly Commons.
It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact mgibney@pacific.~- COMPUTERIZED FORMULATION AND OPTIMIZATION OF MEDICATED CHEWING GUM A thesis presented to the Faculty of the Graduate School University of the Pacific School of Pharmacy Stockton, California In partia,h~fu:tf:iTlment of the requirements for the Degree Master of Science by Dani_eL J. October, 1984 I H--- ~ o---- ti 6------ In Memory of "Tootsie" Berky ACKNOWLEDGEMENTS tl ___ 0 .; I have the unique opportunity and privilege to have a larger than average number of people that I feel should be "'!-·-·--~- given some share in the recognition of this work. First mention should be given to Dr.
Ravirldra Vasavada as his patience and flexibility have greatly aided this study. In addition his successful efforts in assisting me financially are greatly appreciated, and have made all of this possible. I also wish to thank my committee members, Dr. Herschel Frye, Dr.
Richard Jones and Dr. Roy Childs for taking the time out of their very busy schedules to assist me in their areas of expertise. My appreciation is also extended to Dr. Reuben Smith, Dean of Graduate Studies.
There are several people outside the confines of the University who have also been instrumental in keeping this project going. My special thanks to Tom Clark, engineer at Lawrence Livermore Labs who, without regard to personal gain, assumed the responsibility for the "care and feeding" of my TRS-80 computer hardware. Wess Ratcliff, I offer my gratitude for all his vast knowledge about TRS-80 software and programming, and his patient counsel at late hours in the evening. To Alvin Eng, engineering student, my thanks are due for his advice and guidance on getting optimum use of the Burroughs 6700 mainframe computer, and getting me out of those "tough ii ,, _ __ bug~"· ~ - And to all of the above, my warmest thanks for lo:.; __ ,,11"' _ __ something even more precious than their individual contributions, their friendship.
iii ABSTRACT H_ __ ~ Sixty Four caffeinated chewing gum preparations were formulated by varying the amounts of (i) cinnam~ldhyde, (0-0. The gum base consisted of 33.33% yellow beeswax and 66.66% polyisobutylene MH, and was added, adjusting for a final weight of 2 grams per gum. The amount of caffeine was maintained at lOOmg. The preparations were subjected to an in vivo release study as well as a hedonic survey with a panel of student volunteers.
Data were analyzed by using multiple linear regression on a mainframe computer. The resulting mathematical model was used to predict a theoretically ideal formulation, relating various concentrations of the above constituents to a global rating. The results indicated consistant release (90-100%) of caffeine for most formulations, but considerable variation was observed for the hedonic scores. A positive correlation with cinnamaldehyde and flavor was observed, while increased amounts of sugar appeared to lower the overall rating.
The optimum formulation predicted by the model should contain 40% sucrose, 0. ci---- Table of Contents ~------ ABSTRACT. 8 Formulation of Gum. 9 In Vivo Release Study.
16 RESULTS AND DISCUSSION. 18 Statistical Analysis and Optimization 18 Independent Variables. 88 iv Table of Contents •••.• continued TABLES Table (I) Independent Variables ••.••••••••••• 21 Table (II) Descriptive Statistics ••••••.•••••••••••• 24 Table (III) Regression Coefficients. 25 Table (IV) Variables not in the Equation •.
26 Table (V) Condescriptive Statistics .of Independent Variables. 35 Table (VI) ANOVA: European Big Red vs. Ideal For mu 1 at ion. 37 Table (VII) ANOVA: American Big Red vs.
38 Table (VIII) ANOVA: Caffeinated European Big Red vs.Table (XI) ANOVA: Median Base without Caffeine vs I de a l F or rnu 1 a t i on. 40 FIGURES Figure ( 1 ) Contour Plot with Docusa te· at Omg per 2g gum. 2 7 Figure (2) Contour Plot with Docusate at 3mg per 2g gum. 28 Figure ( 3) Contour Plot with Docusate at 5mg per 2g gum •.
29 Figure ( 4) Contour Plot with Docusate at 8mg per 2g gum. 30 Figure ( 5) Contour Plot with Docusate at lOmg per 2g gum. 31 Figure ( 6) v ;_j _ __ Table of Contents ••••• continued Overall Score vs.••• 32 Figure (7) Overall Score vs. 33 Figure (8) Mean Hedonic Scores for Gum Samples •••••••••.
Frequency Distribution of Response on Sweetness. 42 Figure (10) Frequency Distribution of Response on Flavour. 43 Figure (11) Frequency Distribution of Response on Texture. 44 Figure (12) Frequency Distribution of Response on Bitterness.
45 Figure (13) Frequency Distribution of Response on Longevity. 54 Appendix (A) Formulation Program. 54 Appendix (B) Assay Program. 57 Appendix (C) Survey Form.
59 Appendix (D) Composition of Chewing Gum and Results. 62 Appendix (E) Read File Data Program. 78 Appendix (G) Merge Data File Utility. 81 vi H-- Table of Contents •.••• continued Appendix (H) Modem Transfer Program •.
---- ~---~- -- ~~---- In this century we have experienced a revolution in • the treatment of disease. In medicine, the most dramatic developments have been in the creation of new chemical entities. However, in the past decade, the rate of growth for the physician's armamentarium has declined somewhat. Furthermore, in the search for new drugs, vast numbers of prototypes must be rejected.
Fortunately, trends not only change their pace but also their direction. It has become more apparent that the modification of the dosage form of a particular drug molecule can greatly enhance therapeutic benefit. Drugs hitherto discarded due to short duration of action, or peaking of plasma concentrations into toxic ranges, merit a second look as the state of the art for the formulation of new drug delivery systems continues to evolve for new as well as old drugs to optimize their bioavailability and therapeutic efficacy. Another parameter which has recently been recognized to be of cardinal importance is the patient acceptability of the dosage form.
In order to achieve compliance during a medication regimen, especially those of chronic duration, ~--- 0. ~~ 0 H ---- n '-' it is of the highest priority not to detract from the quality of the patient's lifestyle. ~---- -- --- Exactly when man first used natural gums for the purposes of mastication is uncertain, although there are accounts of such use in ancient Greece [1]. Its popularity throughout most of recorded history was greatest in the Mediterranean principally due to an endogenous supply of gum bearing plants such as acacia and tragacanth [1].
In the late nineteenth century, there was an exponential growth in consumption with the advent of a variety of flavoring and sweetening additives. Use of pharmacoactive additives on a large scale first appeared in the 1950's with the almost simultaneous marketing of Aspergum (aspirin) in the United States and clinical use of nicot!ve bearing gum for smoking withdrawal in the United Kingdom [2]. In 1972 various products containing lobeline (a nicotine-like alkaloid) appeared over the counter in the United States for the same indication. They were not very popular as most people in that specific market opted for chewable tobacco.
The Wrigley company test marketed gums containing vitamin D in Europe and the United Kingdom during 1969 on a limited scale.[l] Chewing gum containing medication affords some advantages over conventional tablets and capsules. First, it is an alternative. People requiring frequent dosing 3 intervals will often find themselves having to take a tablet in public, which can be a source of anxiety to a. -,__, ______ - - -_ large number of people, and may attach a stigma of ill health.
It is also a common occurrence, especially for "those on the go" not to have a glass ofwater on hand. Dry swallowing of tablets and capsules can not only be unpleasant, but for some drugs hazardous. Postponing the dose is undesirable from many standpoints; for some drugs the dose interval is critical for maximum therapeutic benefit. In addition, compliance is best assured when a patient adheres to a regular schedule.
The problem is compounded further with multiple dosage regimens. Some drugs have limited bioavailability when given orally. There are several reasons why this may happen. One of these is the "first pass effect" where there is degradation in the liver before the active drug can enter the general circulation.
The organic nitrates used to treat angina pectoris fall into this category. Some other agents such as propranolol and, most notably, pituitary hormones display superior bioavailability through buccal or nasal mucosa. ADH (antidiuretic hormone) is available as a nasal spray and ergotamine is marketed as buslingual tablets. Such potent agents are delivered through this route to insure not only good bioavailability but a rapid onset of action which is not attainable through the conventional oral 4 route.
Other factors can encompass chemical degradation in the stomach and small intestine, or poor absorption through ~------ the gastrointestinal mucosa. The use of chewing gum can take advantage of all the benefits of sublingual absorption while making for better patient compliance. The effectiveness of a gum delivery system is contingent on a host of variables such as the duration of mastication, requiring careful flavor considerations, the hydrophilic-lipophilic properties of the gum base and added ingredients, and last but not least the chemical properties of the drug itself. These same variables are expected to affect the drug release rate as well as the extent to a significant degree.
With the use of chewing gum, the absorption via the traditional gastrointestinal route is not sacrificed and the prolonged presence of the dosage form in the mouth is expected to make the buccal and sublingual routes of absorption more bioavailable as compared with a sublingual tablet. America) developed the Sorbitrate chewable tablet (isorbide dinitrate) to take advantage of these complementary effects. In addition some drugs are intended to impart their action in the mouth. A salient example of this would be nistatin.
The presently available suspension is somewhat 5 ~ ~---------=---- ~ '-' - inconvenient to use, difficult to carry along on one's person and the drug is not present at the desired site of ·-- ,__, _ _-_-- _-_- action for a prolonged period. ~----- With chewing gum preparations, special attention must be given to the masking of the unpleasant taste of the drug. This is even more critical than with other flavored dosage forms, such as oral liquids because of the relatively long duration of exposure to the gustatory receptors in the mouth. With the remarkable progress made in innovative dosage forms, the techniques and tools available to the formulator have undergone a revolutionary change as well.
Electronic data processing can analyze and assimilate vast quantities of data and is rapidly becoming an invaluable instrument in systematically optimizing a pharmaceutical formulation oncEO the parameters are defined. It is hoped that this study will not only lay the ground work for an exciting new dosage form, but demonstrate the merits of pursuing a multidisciplinary approach to problem solving.:i EXPERIMENTAL Design Although drug delivery systems such as chewable or sublingual tablets have been utilized in the past for drug delivery, the use of chewing gum as a drug delivery system has not been fully investigated.