This invention relates to process for the production of coated Doxycyc1ine Hyclate pellets and more particularly delayed release capsules.
The pellet has a dissolution rate in vitro, which when measured according to the Paddle Method of U.S. Pharmacopoeia XXIII, is not. more than 50% of the doxycycline after 20 minutes of measurement in a 0.1 N HCI medium. Not less than 907. of the doxycycline is relased after a total of 30 minutes measurement in a buffer medium of pH 5.5.
Doxycycline is indicated in infections caused by Gram negative micro-organisms like Haemophilus Ducreyi (Chancroid), Yersinia pestis (formerely Pasteurella pestis), Francisella tularensis (formerely Pasteurella tularensis), Bartonella bacilliformis, Bacteroides species, Vibrio cholerae (formerely vibrio comma), Shigella species, Haemophilus influenzae, Campylobacter fetus (Vibrio fetus), Brucella species in conjunction with streptomycin, E. coli, Enterobacter aerogenes (Physician Desk Reference 1995; 49 1839-1839).
Doxycycline is indicated for treatment of infections caused by Gram-positive microorganisms when bacteriological testing indicates appropriate susceptibility like Streptococcus species, Diplococcus pneumoniae, Staphylococcus aureus, Treponema pallidium, Listeria, Clostridium species, Bacillus anthrasis, Actinomyces species (Physicians Desk Reference 1995; 49 1838-1839).
Doxycycline has also been found to be useful in some of the conditions like acute intestinal amoebiasis, acne, trachoma, uncomplicated uretheral, endocervical or rectal infections, nongonococcal urethritis and uncomplicated gonococcal infections.
Although tetracycline has a low side effect profile, they may produce varying degrees of gastrointestinal irritations. One tetracycline congener, doxycyc1ine, synthetically derived from, axytetracyc1ine is virtually completely absorbed from the upper gastrointestinal tract. (907. to 1007.). (Richard S» Eierger MD, J Clin. Pharmacology 1984; 150; 689-694).
Tetracycline are bacteriostatic agents that inhibit the growth of susceptible Gram-postive bacteria and a.re the drugs of choice for infections caused by Rickettsiae, Chalamydia and Mycoplasma pneumonia.
Many side effects are associated with the upper gastrointestinal tract such as anorexia, nausea, vomitting, abdominal discomfort and decreased apetite.
Nausea and vomiting have been reported in approximately one-third to one-half of patients receiving Doxycycline in clinical studies. (Grimer Da, Schulz Kf, Gates W Am. J. Obstet. Gynecol. 1984;150;689-694). (Bryant Sg, Fisher S. Kluge RM, Drug Intell. Clin.Pharma. 1986520;471-472).
Many Side effects are associated with the upper gastrointestinal tract such as Anorexia, nausea, vomitting, and stomach of abdominal discomfort and decreased appetite. In a study of adverse drug reactions from antibiotics, 35/113(317.) of patients treated with doxycycline hyclate after questioning reported nausea and vomiting while 24/373(6.47.) spontaneously reported nausea and vomiting. These frequencies where 3-fold higher than those reported with other antibiotics. The tendency of nausea and vomiting have been reported approximately one-third to one-half of patients receiving Doxycycline in clinical studies.
Another side effect of doxycycline hyclate is esophageal ulceration, if the capsules for some reason do not reach the stomach but. remain in the oesophagus. A solution to these problems has been attempted by the introduction of doxycycline hydrate (base). This new formulation has eliminated the above mentioned side effects, but it soon became apparent that the bioavailability in a number of patients, which were also in treatment with antacids and the like, was significantly reduced. This can be explained by the lack of acid production in the stomach being the cause of reduced dissolution of doxycycline hydrate. An increased pH of the stomach decreases the bioavailability of doxycycline monohydrate.
The enteric coated pellet formulation of doxycycline have been shown to have a reduced (approximately 50%
reduction) rate of nausea and vomiting.
Therefore the present invention relates to delayed release coating of Doxycycline Hyclate Pellets to overcame the side effects associated with the upper gastrointestinal tract (site of absorption of doxycycline). This invention also includes within its scope a method for the production of these delayed release pellects.
Additionally, Doxycyc1ine hyclate has a long half-life of 20-22 Hrs., thus permitting once daily administration after initial two doses on the first day of therapy. This represents an advantage over other tetracyclines. This invented product is very effective in the treatment of respiratory tract infections through a convenient once daily dosage. This product can also be used for genito-uninary, dental. Ear, Nose & Throat and gynecological infections, inclusion conjunctivitis.
Delayed release coating materials, while satisfactory, suffer a major disadvantage is that. these are not soluble at site of absorption of Doxycyc1ine. Delayed release coating material which we have used in our invention is Hydroxy Propyl Methyl Cellulose* phthalate which is soluble at the site of absorption of Doxycycline and therefore a high efficacy is achieved.
A process for the manufacture of delayed release pellets/capsules of Doxycycline hyclate comprising.
Doxyeyeline hyclate pellets are manufactured by blending together Doxycycline hyclate, ingredients and excipients as here in described to from a blend, Granulating said said blend to form a granulated mass with hydroalcohol ic solution, saxid granulated mass passed through an extruder fallowed by spheronization and said pellets sprayed under controlled conditions, the temperature of the inlet air to the fluid bed coater kept at. 56C, product temperature maintained at 37C and outlet air temperature kept at 36C, finally coated pellets were dried in fluid bed coater for 10 to minutes.
SUMMARY OF THE INVENTION
Accordingly, a primary object of this invention is to provide a simple process of making Doxycycline Hyclate Pellets using extruder, spheronizer and theraby coating the pellets for delayed release with Hydroxy Propyl Methyl Cellulose phthalate using fluid bed coater After coating. It complies with the given standards of United States Pharmacopeia-23 monograph of Doxycycline Hyclate delayed release pellets as follows :-
A is not more than 507. of the doxycycline is released after 20 minutes of measurement in a 0.1. N HCI medium.
B Not less than 907. of the doxycycline is released after a total of 30 minutes of measurement in a buffer medium of pH. 5.5.
The object of this invention is to provide doxycyc 1 ine in delayed release from;, which overcomes all the side effects of upper gastrointestinal tract & there is no reduction in drug release. This is expected to result in less toxicity problems and more effective therapeutic activity.
DETAILED DESCRIPTION OF THE INVENTION.
According to the process of this invention, whole process has been divided into two steps.
1. Pelletisation of Doxycyc1ine HCI powder using extruder and spheronizer.
2. Provide delayed release coating on these pellets using fluid bed coater.
Far making pellets, the ingredients are s
Lactose National formula, Microcrystalline Cellulose National Formula, Poly Vinyl Prolidone United States Pharmacopeia, Crossmellose sodium National Formula, Lauryl sulfate National Formula, Starch National Formula, and sodium. Starch Glycolate National Formula, di calcium phosphate, sodium carboxy methyl cellulose, Polysorbate 80 National Formula, Colloidal Silicone Dioxide National Formula, Doxycycline Hyclate United States pharmacopeia.
For the delayed release coating of these pellets, the enteric polymer component may be any one or more of
the following polymers: Cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimel1itate, hydroxypropy1 methylcel lulose phthalate, hydroxypropy1 methlcellulose acetates, dioxypropyl methyl cellulose succinates, acrylic methay lie acid copolymers, shellac, cellulose acetate phthalate and mixtures thereof. The at least. one plasticiser may be selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol, glycerol and mixtures thereof. It will be understood that the plasticiser used may be largely dictated by the polymer used in the coating formulation. Other ingredients are Talc United States pharmacopeia, Ponceau 4R, Isopropyl Alcohol United States Pharmacopeia, Methylene Chloride National Formula.
The pelletised pharmaceutical composition of claim 2 wherein the core coating comprises approximately 2.5. to 307. by weight of a plasticiser seleted from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol, glycerol and mixtures thereof.
A method for preparing a pelletised sustained released pharmaceutical composition, comprises providing.
a core element comprising
approximately 0.1 to 957. weight, based on the total weight of the core element of an active ingredient, approximately 0.1. to 557. by weight of a binding agent;
a core coating for the core element, including approximately 30 to 977. by weight, based on the total weight of the core coating, excluding, filler, of mi en teric po1ymer
approximately 3 to 507. by weight of an insoluble polymer, the enteric polymer comprising at least.
approximately 707. by weight of the total weight of the enteric polymer and insoluble polymer
The present invention will now be more fully described with reference to the accompanying examples. It. should be understood, however, that the following description is illustrative only and should not be taken in any way was as restriction on the generality of the invention specified above
Fig. 1 Flow chart depicting manufacturing of Doxycyc1ine-DR Pellets.
(Figure Removed)
Hydroxy Propyl Methyl Cellulose phthalate is the preferred polymer because of its solubility at pH 5.5, compatiability with the active and inactive ingredients and its inertness. The at least one plasticiser may be selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethlene glycol, glycerol and mixtures thereof. It will be understood that the plasticiser used may be largely dictated by the polymer used in the coating formulation.
A typical Hydroxy Propyl methyl cellulose phthalate coating solution may comprise of 6 to 107. by weight of the pellets. The coated pellets were dried in fluid bed coater itself for 10 to 15 minutes. The release pattern obtained complies as per United States pharmacipeia.
EXAMPLE 1.
Composition Per capsule (mg.)
Doxycycycline Hyclate 117 mg.
Micro Crystalline Cellulose United States Pharmacopeia 66mg .
Lactase National Formulation 60 mg.
Starch National Formulation 16 mg.
Sodium Starch Glycolate National Formulation 10 mg.
Sodium lauryl Sulfate National Formulation 2 mg.
Coliloidal Silicon Dioxide National Formulation S mg.
Crossmellose Sodium National Formulation 9 mg.
Poly Vinyl Pyrolidone United States Pharmacopeia, 3 mg.
Polysorbate 80 National Formulation 5 mg.
Isopropyl Alchol q.s
The required ingredients were blended and granulated with a hydroalcoholic solution. Whole granulated mass passed through on extruded followed by spheronization.
The resulting pellets weredried in an oven. The size of pellets obtained was of mesh size ranging from 14 to
24.
EXAMPLE 2
Decayed release coating of Doxycyciine Hyclate pellets Per Capsule Composition (mg.)
Uncoated Doxycyciine Hyclate pellets from examplel 300 mg..
Hydroxy1 propel methyl cellulose phthalate 28 mg.
Trlacetin National Formulation 6 mg.
.Poly Ethylene Slyco1-400 United States Pharmacopeia 3 mg.
Talc United States Pharmacopeia-National Formulation 3 mg„
Methylene Chloride National Formulation q.s.
Isopropyl Alcohol q.s.
Ponceau 4R. i mg.
Coating solution was prepared using above-mentioned ingredients. Coating solution was sprayed an the pellets loaded in fluid bed coater. All the parameters of fluid bed coater were controlled properly. Temperature of inlet
air kept at 56c., Product temperature kept at 37*C and ou11et air temp. was kept at 36* C.
REFERENCES
1. U. S.. Pharmaceopoeia (1995; Page Mo. 558).
2„ Physicians Desk Reference (1995; 49:1838-1839).,
3. Cuhna BA et al (1982) Therapeutic drug Monitoring 4, 115
135.
4. Ric hard S.Berger. Md, J.CI in, Pharmacol (1988;28:367-370) .
5. Grimer Da, Schulz Kf, Gates W, Am. J. Obstet, Gynecol.
(1984;150: 689-694).
6. Bryant Sg, Fisher S, And Kluge F5m; Drug Intel 1. Clin. Pharma . ( 1986 ; 20 : 471--472 ) »
7. Bogardus JB, Blackwood Rl< (1979). J Pharma Sciences 68, 1183 1184)
8„ Khouzam 8, Yazbeck D (1987). Acta Therapeutica 3, 309-315.
9. Berger RS (1988). J Clin Pharmacol 28, 367-370.
10. Story MJ, MCCloud PI, Boehm 6 (1991). Eur. J Clin
Pharmacol 40, 419-421.

WE CLAIM:
1. A process for the manufacture of delayed re1ease pe11ets / capsu1es of Do xycyc1ine hyc1atecom prising ,
blending doxycycline hyclate, conventional ingredients,, and excipients as here in described to form, granulated mass
with hydroalcoholic solution, said granulated mass is passed t h r o u g h an e x t r u d e r f o 1 1 owed by s p h e r o n i z a t i o n in a manner as herei.n descri bed and said pellets sprayed under controlled conditions as herein described, the temperature

of the inlet air to the fluid bed coater is kept at 56OC,,

product temperature maintained at 37OC. and outlet air
temperature kept at 36C, finally coated pellets so
produced are dried in fluid bed coater for 10 to 15
minutes.
2,. A process as claimed in claim 1 where in coating c o m p i'" i s e s 6 t o 1.0 % b y w e i g h t o f t h e p e 11 e t s and t h e c o r e coating comprises approximately 2„5. to 30% by weight of a plasticiser selected from diethyl phthai ate, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol., glycerol and mixtures thereof„
3. A Process as claimed in claim 1 for the manufacture of delayed release pellats/capsules of doxycycline hyclate substantially as here in described with reference to the examples.