US3080294A

US3080294A - Sustained release type of pharmaceutical vehicles

Info

Publication number: US3080294A
Application number: US63736A
Authority: US
Inventors: Shepard Mark
Original assignee: Key Pharmaceuticals Inc
Current assignee: Key Pharmaceuticals Inc
Priority date: 1960-10-20
Filing date: 1960-10-20
Publication date: 1963-03-05
Anticipated expiration: 1980-03-05
Also published as: GB935602A; CH423100A; NL122039C; BE659324A; DE1467961A1; NL270408A

Description

United States This invention relates to a sustained release type of pharmaceutical vehicle and to the method of its preparation. More particularly, the invention concerns a novel and more efficient seal coating to be employed in the preparation of medicinal carriers within said pharmaceutical vehicle, said vehicle including the carrier in suitable dosage amount and form, as well as forms of tablets, capsules or pellets.

Multicoated sustained release or delayed action type pharmaceutical tablets are known, and one type of such tablet and the method of its manufacture has been described, for example, in US. Patent 2,853,420. The tablet described in that patent is built up by applying to a central core or basic pellet of compressed sugar or corn starch a multiplicity of medicating impregnation layers in a series of successive coating steps. When perhaps 12 medicating coatings have been thus applied, thereby increasing the weight of the core by about 0.75%, the core or pellet as medicated is then successively coated with from 25 to 250 coatings of a sustained or delayed action material, the thickness of the coatings being gauged so as to provide a sustaining factor of approximately one hour for each 25 coatings. This will increase the weight of the tablets another 1.5%. Thereafter, one-tenth of the coated pellets are removed, and the remaining nine-tenths coated with another 25 layers of coating, yielding a product having a sustaining factor of 2 hours. If desired, oneninth of the latter batch can be separated and the remaining eight-ninths coated with another 25 layers to achieve a sustaining factor of 3 hours therefor, and so on. Thus even a 250-layer coated tablet can be built having a sustained action for about hours. The object was to produce a tablet which will postpone or delay action for a period of several hours during which the tablet passes through the stomach into the intestines, and then assure liberation of the medicant for a period of several hours in the intestinal tract.

To achieve the impregnation of the core with medicament, and to apply the successive coating layers, the aforenentioned patent employs a coating composition comprising a solution in 85% alcohol or in chloroform of an ether or ester of cellulose, such as for example, of methylcellulose, ethylcellulose, or cellulose acetate-phthalate. About 10% of beeswax and castor oil is added to promote plasticity and elasticity of the resulting coating. Preferably the coating operation is performed in a rotating pan, a layer of fine talc being applied to each batch while the coating is still soft. Preferably the coating is substantially neutral. A suflicient number of coatings is thus provided to insure predetermined delaying or sustaining action even if individual coatings are imperfect or not homogeneous. The coatings gradually decrease in thickness as they progress from the core in proportion to its distance from the center, and being generally not more than about 1% of this distance.

It is also known to employ as an enteric coating composition, soluble in the intestinal tract and not in the gastric fluids, an inner coating of cellulose acetate-phthalate and an outer coating of beeswax, as a combined coating on a tablet. Conversely, the wax may serve as the inner coating and the cellulose acetate-phthalate as the outer coating. In either case, the combination acts to prevent attack on the medicament in the stomach. However, when the coating is penetrated, there occurs a total release of the medicament. These coatings were applied in the prior art in an amount as much as 8% by weight of the tablet.

Experience has shown that in multicoated tablets of the character described, a sustained release factor based upon number of coating layers per se is not always reliable. Moreover, the cellulose acetate-phthalate-beeswax combination type of coating as presently used in multicoated tablets is ineflicient in that an extremely large number of coatings is required, with resultant expensive and cumbersome processing of the tablets in the course of manufacture.

It is also known to prepare sustained release powders by applying to a powdered medicament a first coating of a fatty material such as a fatty alcohol, a glyceride, or beeswax in an amount ranging from 25% to by weight of the powder, the fatty material being in solution in an organic solvent such as alcohol or chloroform. A secondary coating of the same material or materials may also be applied.

In accordance with the present invention, it has been found that by a careful selection of coating ingredients, and the combination of these ingredients into a particularly useful mixture, the emphasis in coating can be shifted from number of coatings to a percentage increase in weight of the carrier to be coated. Furthermore, in accordance with the invention, the rate of hourly release can be predicated upon such weight increase and not upon multiplicity of coatings, introducing a new concept in this field. This novel concept makes possible the production not only of carriers containing a single active ingredient or medicament, but also of carriers containing two or more medicaments, including incompatibles. It permits the liberation of predetermined amounts of medicament from coated granules which have been prepared either with a single coated medicament surrounding the central core or pellet, or with additional layers of coated medicament, with successive release of the medicaments, which may be additive, synergistic, or antagonistic, after a time lapse, and with no danger of theeir interaction or lessening of their activity in the system of the patient.

In the preparation of the carriers, there is employed as a central core, pellet or granule, a mixture of cane sugar and corn starch, or wheat or potato or rice starch. The mixture is finely ground and worked into approximately round granules in a rotating pan in conventional manner to produce granules or basic pellets having a mesh size between about 10 and 20 mesh. Small pellets of the active medicament may also be formulated as a core. Thus, a given amount of medicament may be coated by spraying with a saturated solution of sucrose, or with a solution of cellulose acetate-phthalate, or with a solution of a pharmaceutical glaze or of a vegetable gum, and then tumbled in a rotating pan while drying with a blast of cool air, followed by screening to 10 to 20 mesh size.

The core pellets are placed in a rotating pan and are subjected to treatment with a solution of an adhesive material in a volatile organic solvent in an amount sufficient to cover the surface of each pellet. There may be employed for this purpose any of the conventionally em ployed adhesives or exci-pients, such as cellulose acetate phthalate or shellac. The volatile solvent may be any solvent which evaporates rapidly leaving no toxic residue, for example, alcohol, ether, acetone, or chloroform. When the surface of the pellets has become tacky owing to evaporation of the solvent, there is added an amount of active ingredient or medicament in the form of a fine powder, sufficient to evenly coat and adhere to the pellet surfaces. This process is continued until the requisite dosage amount of the medicament has been impregnated evenly on the surface of each pellet. Any desired type of medicament may be thus applied, including, for example, =sympathomimetic agents, such as amphetamine or isoproterenol (Isopropyl-Arterenol), anti-biotics, vitamins, minerals, drugs, cardiac agents, barbiturates, and the like. The total weight of medicament employed may approxi- 5 mate the total weight of pellets to be coated. Thus, where a single medicament is applied, it will be used in an amount about equal to the weight of pellets. If several drugs are applied, the total weight of the drugs will approximate the total weight of the pellets. The coating operation can be carried out in any conventional type of equipment, such as, for example, a 36 inch diameter coating pan of the rotating type, operating, for example, at a speed of about 30 r.p.m. The pan is provided with means for admitting a flow of heating or cooling air to its interior. Where the core pellet is a medicament, some of the foregoing steps can be eliminated.

A pellet, prepared as described, and with no additional coating, will, upon oral administration, provide immediate release of the medicament into the stomach of the patient. If desired, however, an enteric coating, such as a solution of cellulose acetate-phth-alate in chloroform may be applied to provide a glaze protective coating on the pellet which is unafiected by stomach juices, but which will dissolve in the alkaline intestinal fluids, releasing the medicament in the intestinal tract. If the cellulose acetate-phthal-ate solution is applied to the medicament-impregnated pellets in an amount of approximately 2 pints per 50 lbs. of pellets, a coating is produced which will withstand the action of the stomach juices for ap proximately one hour, thus providing sufficient time for average passage of the carrier into the intestinal tract.

It is frequently necessary in medication to delay the release of drugs for considerably more than the one hour period provided by the foregoing type of carrier. In such a case the problem becomes one of providing a pellet with a coating or several coatings of a retardant material in an amount suflicient to delay exposure of the medicament to the intestinal fluids for periods of 2 to hours, or more. Moreover, it is often desirable to allow larger dosages to be released at a slower rate, While at the same time controlling the rate of release so that no more than a definite predetermined proportion of the dosage is released in a given number of hours. It may also be desirable to provide means whereby two or more drugs can be released in succession at such time intervals that they will not interfere in their therapeutic action. The successively released drugs may be such that the second may either offset or supplement the first released drug, for example a vasodilator and a vasoconstrictor, or a soporiiic and a stimulant.

These objectives are achieved by the novel coating composition and method of the present invention.

In accordance with the present invention there is provided a novel coating composition which is substantially unaifected by the stomach juices, and whichvretards the action of the intestinal fluids. The novel coating composition is thus enteric in character, but by reason of a slight degree of acidity it serves to neutralize the alkaline intestinal fluid and hence to delay its action on the coat ing. Moreover, the ingredients of the coating impart to the coating a melting point higher than body temperature (98 PR), thereby further providing a retarding o1 delaying action to the effect of the intestinal fluid.

It has been found that the application of the novel coating composition to the core pellet may be regulated so to produce a total increase in weight of the pellet which will result in retardant effect with respect to the intestinal fluid action of approximately one hour. The actual weight increase imparted to the pellet is governed by the known rate of absorption of the medicament to be released in the intestinal tract. Thus, in the case of a slowly absorbedmaterial the Weight increase of a given oa g h d be of the order of magnitude of about 75 5%. In the case of a rapidly absorbed material, the weight increase may be of the order of about 10%. However, for achieving a retardant factor of one hour, it has been found that an average weight increase of from about 7% to about 8%, or approximately 7.5% is generally desirable. Each such increase in weight of the pellet of 7.5% provides an additional hour of retardation in the intestinal tract, so that by applying a succession of coatings each representing 7.5 by weight, delays of 2 to 10 or more hours may readily be attained. If a single drug is applied to the core pellet, the entire amount may be released after a predetermined time of say 4 hours. If the drug layers are divided into two or more portions, a part may be released in 1 hour and the remainder, for example, at any other desired intervals. The same is true if two or more different drugs are employed in a single carrier.

The novel coating composition of this invention, which is only slowly affected by the intestinal fluids, comprises a mixture of not less than about by weight of a glyceride and minor amounts of at least one fatty alcohol and of beeswax. Thus, the glyceride will generally range between about 95 and 99% by weight of the mixture, the fatty alcohol weight between about 0.1% and 0.3%, and the beeswax weight about 0.01% and 0.05%. The respective ingredients are dissolved in a suitable organic volatile solvent and maintained at a temperature suflicient to keep the ingredients in solution.

The glyceride may be any suitable glyceryl ester of a fatty acid or a hydrogenated aliphatic acid, such as, for example, glyceryl monostearate, glyceryl distearate or glyceryl ester of hydrogenated castor oil, but glyceryl monostearate is preferred. The fatty alcohol is any suitable long-chain alcohol, such as cetyl, myristyl, or stearyl alcohol. The beeswax is a purified grade, such as white bleached beeswax.

The proportions of these ingredients are correlated with the speed of absorption of the medicament, and with the final weight of the carrier. Thus, if the final weight of the carrier is between 300 and 600 mg, a preferred coating composition in accordance with the invention would comprise:

Weight per Ingredient: carrier, milligram Glyceryl monostearate 45-55 Cetyl alcohol 0.25-0.75 Myristyl alcohol 0.25-0.75 Bleached white beeswax 0.005-0.24

However, if a slowly absorbed medicament is used, the

following coating composition would also give satisfactory results:

Weight per Ingredient: carrier, milligram Glycerol ester of hydrogenated castor oil 65-70 Cetyl alcohol 0.25-0.75

Myristyl alcohol 0.1-0.5

Bleached white beeswax 0.15-0.25

EXAMPLE 1 A tablet containing 250,000 units of penicillin (for example in the form of benzylpenicillin sodium) is manufactured by treating a weighed amount of basic pellets with an adhesive solution having the composition:

6 completed, the 160 lbs. total of portions 3 to 10 inclusive will have increased in weight by approximately 64 lbs., yielding a total weight of approximately 224 lbs. Portion It will be seen from Table 1 that, starting with 200 lbs., the A and portions each weigh 20 lbs. and are set aside, leaving 160 lbs. of medicated pellets which are to be treated with the wax solution. When this treatment is 75 5322 22 acetate'phthalate i 33: 2 is now blended in and the combined portions 2-10 are 0 p 5 treated with 1 gallon of cellulose acetate-phthalate soluand impregnating said pellets with layers of the penicillin tion, yielding at this point a total weight of 224 lbs. plus medicament until a predetermined amount of the medica- 20 lbs. of portion 2, plus 1 lb. of cellulose acetate-phthalate ment has been evenly placed upon each pellet surface. contained in the 1 gallon of its solution, or a total of 245 Thus, 99 lbs. of pellets are combined with 99 lbs. of lbs. The first portion removed, or 20 lbs., and not further penicillin by the use of 2 gallons of the above adhesive treated, is now added, making a total of 265 lbs. of solution, containing 2 lbs of solids, thus yielding a total completed pellets, which can be used as such, or further Weight of treated and coated pellets of 200 lbs. The converted into tablets or capsules as desired. Thus, in acetone evaporates, leaving the cellulose acetate-phthalate accordance with this procedure, portions 2-10 are further on the pellet surfaces. A one-tenth portion (#1) by treated with cellulose acetate-phthalate solution only after Weight of the medicinally treated batch is removed and the application of the wax solution to portions 3-10 is set aside, pending additional treatment of the remaining completed. The amount of cellulose acetate-phthalate ellets. Another portion (#2) totaling by weight the solution used for the application of finishing coatings on balance of the medicated pellets is also removed and set portions 2-l0 is 1 gallon, thereby adding but 1 lb. to the aside. The remaining weighed medicinally treated pellets overall weight of the treated pellets. For conversion into are further treated with a solution of wax-like texture as tablets, selected portions or all portions together may be described previously, until the weight has been increased mixed with suitable amounts of filler, binder, and lubriby 7.5%. When completed, a /a portion (#3) of the cants and compressed into tablet shapes. medicinally treated Wax-like covered pellets is removed Upon ingestion, the tablet will disintegrate and release and set aside. Further additional processing with the the entrapped pellets. Pellets of portions #1 will release wax-like coating solution is continued and applied to the penicillin immediately upon ingestion. Pellets within the remainder of the batch until each achieves another 7.5% tablet f portions #2 through #10 will travel through the weight increase. The wax solution employed has the stomach (gastric media contact) without any noticeable composition: change until entering the intestinal tract, whereupon pellets v E from portions #2 through #10 will dissolve their surface Gbceryl monostearate 900 coatings (cellulose acetate-phthalate and acetone) and Cetyl alcohol do 25 0 th rk a lviyristyl alcohol d0 25 exp Se elf Wax 1 e Bleached White beeswax do 10 The pellets from portion #2 Wlll expose the pen1c1ll1n chloroform 1 for absorption having no wax-like resistance against alkali (intestinal media) as have pellets #3 through #10. The waxy ingredients are dissolved in the chloroform and During further stages of the digestive process, pellets maintained at a temperature between 65 and 67 C. from #3 portion will release penicillin for absorption with- When the medicament has a slow rate of absorption, a in the next hour, and each succeeding hour of digestive wax solution may be employed which has the composiprocess Will further break down the wax-like coating tion: substances and allow the penicillin to be released in ac- Glycerol ester of hydrogenated castor oil grams 900 40 Egg??? g i d gi i i i of wax"hke matenal Cetyl 31501101 d6 25 P ac P6 Myristyl alcohol do 25 EXAMPLE 2 fi White beeswax g; Utilizing the method as described in Example 1, two

0m medicaments may be incorporated into the pellet struc- Portions of weighed amounts totaling /6, A, ture. Medicaments usually antagonistic to one another /5, V2 (one-half) and balance are removed upon comcan be commonly used and incorporated into an overall pletion of each 7.5% increase in weight over the prevehlcle, be it tablet, capsule 0r p p r viously removed portion. After coating the basic pellet with a medicament such The sequence of steps is summarized in the following as dextro-amphetamine sulfate, the medicated pellets are I T bl 1; treated with the wax-like coating solutions to sustain Table 1 SCHEDULE FOR TREATMENT OF PELLETS Addition of Pellets removed Weight in Coatings I from Pan Weight Portion lbs., Start Weight 1.11 pounds No. of each after remainstep Percent Weight Coating Propor- Weightin ingiu Weight in tion lbs. pan Increase Pounds 1/10 20.0 180.0 1/9 20.0 160.0 7. 5 1/8 1 21.50 150. 50 7.5 1/7 23.1125 138.6750 7.5 1/6 24.8459 124.2297 7.5 1/5 26.7094 106. 8375 7.5 1/4 28. 7128 86.1377 7.5 1/3 30. 8660 61.7320 7.5 1/2 33.1810 33.1809 7. 5 All 1 35. 6695 Portions 2-10 to be treated further after blending. Weight of portions 2-10 will be activity after ingestion, for a predetermined time. Each hourly determination is accomplished by every 7.5% increase in weight of wax-like coatings added to the pellets.

In the case of an eight-hour sustaining factor, the

7, amount of wax-like coatings applied would result in a weight increase of 60%. In the case of a four-hour sustaining factor, the amount of wax-coatings applied would show a resultant increase in weight of 30% over the original medicated pellets.

When intestinal time factor is achieved, several coatings of OAR-acetone solution are applied over the waxcovered pellets and the second medicament is applied to the pellet surface (phenobarbital or other type sedative). The pellets are dried prior to being placed into vehicle of choice.

Upon ingestion, be it tablet, capsule or pellet, per se, the latter medicament would be released immediately (phenobarbital or other type sedative) and upon the pellets exposing the C.A.P.-acetone coating in the stomach, no noticeable change would occur until the pellets reach the intestinal tract.

The C.A.P.-acetone coating dissolves when in contact with intestinal fluids (alkali) and exposes its wax-like coating, which will dissolve in accordance with the hourly factor given same by the 7.5% series of Wax-like coating increases.

When proper time interval is reached the existing pellets will release the former medicament (dextro-amphetamine sulfate) and the resultant therapeutic activity will take place, this activity being antagonistic to the activity caused by the first medicament released.

This process may be reversed and time interval of antagonistic activity can be controlled in accordance with the amounts of series of wax-like coatings utilized in the pellet treatment.

EXAMPLE 3 Medicaments such as salicylates, ferrous compounds, Zoxazolamine and phenylbutazine, which tend to cause discomfort when in contact with the stomach and when oft times have to be taken every four hours for therapeutic results, fall within the scope of this invention.

The medicament is coated upon the core pellet, or the core pellet can be made of the medicament itself, and then treated with a series of a four-hour duration, with the wax-like textured coating. Another dosage of medicament may be applied at this stage over the medicated wax-treated pellets, and another series of wax-like coatings may be applied say for another four-hour duration.

This pellet will release active medicament at every fourhour interval. Still another series of wax-like coatings is further added to the pellet surface to sustain activity for an additional four hours in the intestines. The last dosage of medicant is applied over this wax-like coating, and the pellet is sealed with C.A.P.-acetone solution. The pellets are then dried and placed into proper vehicles (tablets, capsules or the pellets, per se).

Upon ingestion the vehicle will release its pellets. The pellets Will pass through the stomach without any noticeable change and then enter the intestinal tract.

In the intestinal area, the C.A.P.-acetone covering is dissolved and a dosage of medicaments is released for absorption, exposing the outer series of wax-like coatings which will slowly dissolve and expose the second layer or dosage of medicaments for absorption at the fourhour sustaining period.

Intestinal activity will then again slowly dissolve the inner layers of wax-like materials and retard the release of the innermost layer of medicament or the medicated core itself for the next four-hour period. When the retardant wax-like coatings are dissolved, the medicament is available for absorption. ,7

This example illustrates the scope of the invention by allowing three distinct dosages of medication to be incorporated into each individual pellet. 'Ihe medications being of a type incompatible with gastric activity, by utilizing this invention we eliminate discomfort to the patient and allow the individual to ingest one tablet, capsule or fixed amount of pellets, per se, instead of three individual dosage forms.

EXAMPLE 4 Utilizing the method as set forth in Example 1, larger doses of medications may be incorporated into tablets, capsules or pellets, per se.

Where recommended doses of medication call for specific amounts in any one hour (Isopropyl Arterenol Hydrochloride-5 mgm.), this example falls within the scope of the invention.

Normally, tablets containing the exact amount of medication are taken by the patient in accordance with the physicians instructions and with the recommended dosage as stated.

Pellets containing overall larger dosages are fabricated in accordance with the concept as set forth in this invention. These pellets are coated with enough medicament to construct a tablet or capsule or fixed amount of pellets, per se, to total 40 mgm. of active medicament (Isopropyl Arterenol Hydrochloride).

Upon ingestion, the unprotected medically coated pellets, which comprise of the overall batch of treated pellets, will release their portion of medicant for absorption (4 mgm.) within the first hour. The remaining 7 of the pellets (36 mgm.) pass through the stomach unchanged due to its protective gastric coating (C.A.P.- acetone coating) and upon entering the intestinal tract, said coating will dissolve.

The original portion of pellets which has not been treated with the retardant wax-like coatings exposes its medicament for absorption GA; of 36 mgm.=4 mgm.) within the second hour.

The third hour after ingestion allows the original Ms portion of the pellets, which contains but one series of 7.5% wax-like coating sustaining factor, to dissolve its coating in the intestines and releases its medication for absorption A3 of 32 mgm.=4 mgm.).

The next hour of intestinal activity will enable the portion to release its medication (V; of 28 mgm.=4 mgm.).

Still further, the next hour of intestinal activity will allow the /6 portion of the originally treated pellets to release its medication (Ms of 24 mgm.=4 mgm.).

Intestinal activity continues and each hour of said activity will enable another portion of pellets to release its medicant. The sixth hour releases the portion (Vs of 20 mgm.=4 mgm.). The seventh hour exposes the medicant of the original portion of pellets of 16 mgm.=4 mgm.). The eighth hour exposes the medicament of the /3 portion of the original pellets of 12 mgm.=4 mgm.). medicament of the /2 portion of the original batch to expose itself for absorption 0/: of 8 mgm.=4 mgm.), and the tenth hour will allow the remainder of the pellets (4- mgm.) to be absorbed.

The scope of this invention enables larger doses of medicant to be incorporated into one dosage, from pellets made into a tablet, capsule or the pellets, per se, in weighed, calculated amounts, and yet releases in any one hour not more than the recommended dosage, as determined by common practice.

I claim:

1. A sustained release type pharamaceutical pellet comprising an inner core coated With a member of the group consisting of sucrose, cellulose acetate-phthalate, pharmaceutical glazes and vegetable gums and having at least one surrounding layer of a medicament thereon, a coating upon each medicament layer comprising a mixture of not less than about by weight of said coating of a glyceride of a long chain aliphatic carboxylic acid, and minor amounts of at least one long chain fatty alcohol and of beeswax, the weight of each coating being between about 5% and about 10% by weight of that portion of said The ninth hour will enable thepellet coated thereby, each such coating providing approximately an hourly increment of sustainment.

2. A sustained release type pharmaceutical tablet comprising a mixture of pellets as claimed in claim 1, said tablet having a sustainment time of at least one hour.

3. A sustained release type pharmaceutical pellet comprising an inner core coated with a member of the group consisting of sucrose, cellulose acetate-phthalate, pharmaceutical glazes and vegetable gums and having at least one surrounding layer of a medicament thereon, a coating upon each medicament layer comprising a mixture of not less than about 95% by weight of said coating of a glyceride of a long chain aliphatic carboxylic acid, and minor amounts of at least one long chain fatty alcohol and of beeswax, the weight of each coating being about 7.5% by weight of that portion of said pellet coated 10 thereby, each such coating providing approximately an hourly increment of sustainment.

References Cited in the file of this patent UNITED STATES PATENTS 2,853,420 Lowey Sept. 23, 1958 2,881,085 Endicott et al Apr. 7, 1959 2,887,438 Cooper et al May 19, 1959 2,928,770 Bardani Mar. 15, 1960 2,954,323 Endicott et al Sept. 27, 1960 2,956,926 Grief Oct. 18, 1960 OTHER REFERENCES Gross et a1.: Transformulation to Film Coating," in Drug and Cosmetic Industry (D.C.I.) 86 (2), pp. 170- 171, 264, 288-291, February 1960.

Claims

1. A SUSTAINED RELEASE TYPE PHARMACEUTICAL PELLET COMPRISING AN INNER CORE COATED WITH A MEMBER OF THE GROUP CONSISTING OF SUCROSE, CELLULOSE ACETATE-PHTHALATE, PHARMACEUTICAL GLAZES AND VEGETABLE GUMS AND HAVING AT LEAST ONE SURROUNDING LAYER OF A MEDICAMENT THEREON, A COATING UPON EACH MEDICAMENT LAYER COMPRISING A MIXTURE OF NOT LESS THAN ABOUT 95% BY WEIGHT OF SAID COATING OF A GLYCERIDE OF A LONG CHAIN ALIPHATIC CARBOXYLIC ACID, AND MINOR AMOUNTS OF AT LEAST ONE LONG CHAIN FATTY ALCOHOL AND OF BEESWAX, THE WEIGHT OF EACH COATING BEING BETWEEN ABOUT 5% AND ABOUT 10% BY WEIGHT OF THAT PORTION OF SAID PELLET COATED THEREBY, EACH SUCH COATING PROVIDING APPROXIMATELY AN HOURLY INCREMENT OF SUSTAINMENT.