The present invention relates to a process for preparing controlled release pharmaceutical compositions of 7-dimethylamino-6-deoxy-6-demethyltetracycline (minocycline) or non-toxic acid addition salts thereof. More particularly, it relates to a once-a-day delivery system for minocycline, which maintains its therapeutic plasma concentrations in a patient for twenty-four hours.
Minocycline and its non-toxic acid addition salts are widely used in therapy primarily for their antimicrobial effects. The preparation of minocycline is disclosed in US Pat. No. 3,148,212 and US Pat. No. 3,226,436.
Minocycline hydrochloride, a pharmaceutically acceptable salt of the drug, has been available in the United States in the form of immediate release oral capsules containing 100mg of the drug. It is typically administered in doses of about 200mg initially followed by 100mg every twelve hours; or 200mg initially followed by 50mg every six hours in human beings. Oral dosage units typically comprise from about 50mg to about 100mg of minocycline hydrochloride.
Minocycline is absorbed at different rates in different portions of the gastrointestinal tract. Traditional pharmaceutical forms and traditional delayed release forms containing minocycline require frequent ingestion of multiple doses per day, resulting in wide variations in serum concentration throughout the course of treatment, and in poor patient compliance. There have been many attempts to prepare controlled release formulations of minocycline, with varying degrees of success.
US Pat. No. 5,283,065, assigned to American Cyanamid Company discloses a controlled release pharmaceutical composition in oral tablet dosage form comprising two types of granules, active granules and compressible granules. The active granules comprise the active ingredient blended with a diluent and the compressible granules comprise a mono- or disaccharide in a diffusible matrix. The compressible granules distort and fill voids to provide a cushion to prevent the active granules from breaking during tabletting process. This guards against any loss of controlled release properties.
US Pat. No. 5,413,777, also assigned to American Cyanamid discloses a pulsatile once-a-day delivery system which maintains therapeutic blood level concentrations of minocycline in a patient for twenty-four hours by once-a-day administration of custom
designed formulations comprising an initial loading or first pulse of minocycline powder or minocycline containing coated or uncoated quick release granules and a secondary loading or second pulse of minocycline containing pH sensitive polymer coated spherical granules, administered either simultaneously or separately up to about 120 minutes apart.
Most of the approaches used by the prior art are either based on the use of enteric polymers or on preparing different types of granules, which makes the process complicated, expensive and time-consuming.
We have now discovered that once-a-day minocycline composition, which maintains therapeutic blood level concentrations of the medicament in a patient for twenty-four hours, can be formulated as a hydrophilic matrix, which slowly releases the active agent over a prolonged period of time.
A formulation which incorporates the drug in a hydrophilic matrix is desirable due to its ease of manufacture, low incidence of lot to lot variability and relative cost -effectiveness, to provide therapeutic plasma levels of the antibiotic for about twenty-four hours when administered once-daily.
In one general aspect, a process is provided for preparing hydrophilic matrix pharmaceutical compositions of 7-dimethylamino-6-deoxy-6-demethyltetracycline (minocycline) or non-toxic acid addition salts thereof, which maintains therapeutic blood level concentrations of the medicament in a patient for twenty-four hours.
In another general aspect, a process for preparing a controlled release formulation of minocycline is provided which is simple and economical.
The term hydrophilic matrix, as used herein, refers to a uniform mixture of the minocycline, hydrophilic polymers and optionally other excipients.
According to one of the embodiments, hydrophilic polymers include cellulose derivatives such as hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose or combinations thereof.
Improved release can also be obtained by mixing polymers with different swelling properties like hydroxypropyl methylcellulose and sodium carboxymethylcellulose or by using the different viscosity grades of the same polymer e.g. mixture of low and medium viscosity grades of hydroxypropyl methylcellulose or hydroxypropyl cellulose.
Embodiments of the composition further include that the hydrophilic polymers may be characterized by their viscosities in a 2% w/w aqueous solution as low viscosity (less than about 1,000 cPs), medium viscosity (about 1,000 cPs to about 10,000 cPs), and high viscosity (greater than about 10,000 cPs).
Examples of hydroxypropyl methylcellulose polymers of a low viscosity grade include those available under the brand names Methocel E5, Methocel E-15 LV, Methocel E50 LV, Methocel K100 LV and Methocel F50 LV whose 2% by weight aqueous solutions have viscosities of 5 cPs, 15 cPs, 50 cPs, 100 cPs and 50 cPs, respectively. Examples of hydroxypropyl methylcellulose polymers having medium viscosity include those available under the brand names Methocel E4M and Methocel K4M both of whose 2% by weight aqueous solutions have a viscosity of 4000 cPs. Examples of hydroxypropyl methylcellulose polymers having high viscosity include those available under the brand names Methocel K15M and Methocel K100M whose 2% by weight aqueous solutions have viscosities of 15,000 cPs and 100,000 cPs, respectively.
The polymer concentration depends on the type of polymer used, e.g. hydroxypropyl methylcellulose polymers may be present in the pharmaceutical composition of the present invention in an amount from about 5.0% to 25.0% by weight.
The hydroxypropyl cellulose polymers that may be used include, for example, polymers available under the brand names Klucel™ and HPC™, available from Aqualon and Nippon Soda Co. Hydroxypropyl cellulose polymers available under the brand names Klucel EF, Klucel LF, Klucel JF and Klucel GF whose 2% by weight aqueous solutions have viscosities less than 1000 cPs and are examples of low viscosity hydrophilic polymers. Hydroxypropyl cellulose polymer available under the brand name Klucel ME whose 2% by weight aqueous solution has a viscosity in the range from 4,000-6,500 cPs is a medium viscosity hydrophilic polymer. Hydroxypropyl cellulose polymers available under the brand names HPC-SL, HPC-L, and HPC-M whose 2% by weight aqueous solutions have viscosities of 3-6 cPs, 6-10 cPs, and 150-400 cPs,
respectively, are examples of low viscosity hydrophilic polymers, while HPC-H has a viscosity of 1,000-4000 cPs and is an example of a medium viscosity hydrophilic polymer. The hydroxypropyl cellulose polymers may be present in an amount from about 5.0% to 25.0% by weight.
In addition to the active and hydrophilic polymers, the hydrophilic matrix may additionally contain other excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, disintegrants, colorants or flavoring agents.
Diluents may be selected from any conventional diluent such as lactose, microcrystalline cellulose, starch, calcium hydrogen phosphate, sucrose and mannitol.
Binders may be selected from starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose and hydroxypropyl cellulose.
Lubricants may be selected from talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate.
Glidants may be selected from colloidal silicon dioxide (aerosil) or talc.
Suitable coloring or flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
In one of the embodiments, the hydrophilic matrix may be formulated by any pharmaceutically acceptable technique that achieves uniform blending, e.g. dry blending, wet granulation, compaction and fluid bed granulation.
The pharmaceutical compositions may be administered orally in the form of pellets, beads, granules, tablets or pills. The tablets can be prepared by techniques known in the art such as direct compression, wet granulation, fluid bed granulation or compaction. Tablets and pills can additionally be prepared with non-functional coatings. The coating generally comprises film-forming polymers such as cellulose ethers, acrylic
polymer or a mixture of polymers. The cellulose ethers according to this invention may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like.
As noted above, the invention resides in the discovery that a matrix formulation will maintain therapeutic levels of minocycline over a 24-hour dosing period, thus providing once daily dosing. In order to obtain this benefit, it is necessary for the once-a-day minocycline dosage form to achieve certain pharmacokinetic parameters, when compared to a twice-a-day minocycline dosage form.
Peak plasma concentration (Cmax) for once-a-day minocycline (OD) dosage form of the present invention is comparable to the Cmax for a twice-a-day (bid) dosage form of commercially available Minocin ® currently marketed by Lederle Laboratories, when each is evaluated in fasting subjects.
In addition to equivalent peak levels, it is also important that the total amount of the minocycline absorbed from the OD dosage form should not differ significantly, when compared to a bid dosage form over a 24-hour dosing interval. Methods for quantifying drug absorption are well known to those skilled in the art.
Area under the plasma concentration-time curve (AUC) for the OD dosage form of the present invention is comparable to the AUC of the bid dosage form of Minocin ®, when each is evaluated in fasting subjects over a 24-hour period.
An AUC of at least 80% is achieved with the formulations of this invention, when compared to a bid dosage form over a 24-hour interval. Values below 80% tend to negatively impact trough levels leading to sub-therapeutic concentrations of minocycline and loss of antimicrobial activity. AUC in excess of 125% should also be avoided. Thus with respect to the extent of absorption, the pharmaceutical composition of the present invention release the comparable amount of drug with respect to the commercially available bid dosage form.
EXAMPLE 1
This example illustrates the preparation of controlled release tablets of minocycline having compositions as given in Table 1.
Hydroxypropyl methylcellulose medium viscosity grade and hydroxypropyl methylcellulose low viscosity grade were loaded into a mixer and dry blended with minocycline hydrochloride. Microcrystalline cellulose and lactose were added and the mixture was further blended for 10 minutes. The blend was granulated using mixture of Isopropyl alcohol and water until proper granulation was obtained. The granules were dried, ground and sifted to appropriate size.
Talc, magnesium stearate and colloidal silicon dioxide were screened and blended with dried granules. The final blend was then loaded into hopper and compressed into tablets.
Four different formulations I, II, III and IV were prepared according to the general method described above. The compositions for different tablet formulations are given in Table 1.
Table 1: Compositions for different tablet formulations.
(Table Removed)
EXAMPLE 2
Pharmacokinetic evaluation of once-a-day controlled release pharmaceutical composition of minocycline hydrochloride:
The bioavailability study to determine the concentration time plasma profile was done on healthy subjects. The study was conducted by a Phase I, single dose, open, randomized, three period, balanced cross over design described below.
Twelve (12) healthy adult subjects were enrolled and all of them completed all phases of the study. The mean age of subjects of the study was 28 years (range: 21 to 35 years). No drugs including the over-the-counter drugs were allowed 72 hours before or throughout the study period.
Minocycline hydrochloride 200mg once daily controlled release tablets (A & B) corresponded to Formulations I and II of Example 1; and 2 x 100mg of minocycline capsules (Minocin ®) currently marketed by Lederle Laboratories corresponded to the Reference Formulation (C).
The study was divided into three periods with one-week wash-out interval separating each period. Subjects were randomized into three equal groups, which were then randomly assigned to either dosage regimen A, B or C. Dosing regimen sequence followed a three by three Latin Square design where three regimen sequences were employed. The dosing regimens A, B and C were as follows:
Regimen A: (1 x 200mg) 'A' tablets were administered as a single oral dose with 240 ml
of water following a 12-hour overnight fast.
Regimen B (1 x 200mg) 'B' tablets were administered as a single oral dose with 240 ml
of water following a 12 hour overnight fast.
Regimen C (2 x 100mg) 'C' Minocin® capsules were administered, one at 0 hours with
240 ml of water following a 12 hour overnight fast and the other after 12 hours with 240
ml of water, following 2 hour fast.
The blood samples (6 ml) were collected prior to dosing (0 hour) and at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0 and 24.0 hours after each dose. Plasma samples were assayed for minocycline hydrochloride using a validated high performance liquid chromatographic procedure.
The OD formulations (A and B) in accordance with this invention gave plasma concentration time profile desirable for once-a-day dosage form, in that the peak plasma concentration (Cmax) was comparable to that for the immediate release drug. The total bioavailability of minocycline measured as area under the curve (AUC o-t) was also comparable to that of immediate release capsules given twice daily indicating that all the drug was released from the formulation and absorbed during its transit through gastrointestinal tract.
Pharmacokinetic analysis.
Values for minocycline hydrochloride pharmacokinetic parameters, including observed
Cmax, Tmax, and AUC0-t, were calculated using standard non-compartmental methods.
Table 2 summarizes the pharmacokinetic results obtained after single dosing in the above study (Study No. 61-08).
(Table Removed)
As evident, the therapeutic efficacy of the once-a-day formulation was comparable to the marketed immediate release dosage form of minocycline (Minocin® capsules) given in twice-a-day regimen.
Food Effect Study:
Bioavailability of minocycline 200mg OD formulations prepared according to Example II was compared under fasting conditions and following a high fat meal, in healthy adult male subjects.
The study was conducted as a single dose, two treatment, two period, food effect study in 12 healthy adult male subjects. In each of the two study periods, 6 subjects received a single oral dose of test formulation (formulation II of Example 1) on an empty stomach in the morning and other 6 subjects received the same formulation in the morning, 20 minutes after having the US FDA defined high fat breakfast. The OD after having the US FDA breakfast. The OD formulations were administered with 240 ml of water.
Wash out period of five days separated the doses. The blood samples (5 ml) were collected 1 hour before dosing and at 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 14, 16, 20 and 24 hours after dosing. Plasma samples were assayed for minocycline hydrochloride using a validated high performance liquid chromatographic procedure.
The results of the study are shown in Table 5:
(Table Removed)
The results show that the therapeutic efficacy of the OD formulations under fed conditions was comparable to the therapeutic efficacy under fasted conditions.
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred methods of the present invention may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

WE CLAIM:
1. A process for preparing hydrophilic matrix pharmaceutical compositions of 7-dimethylamino-6-deoxy-6-demethyltetracycline (minocycline) or non-toxic acid addition salts thereof, which maintains therapeutic plasma concentrations of the medicament in a patient for twenty-four hours.
2. The process according to Claim 1 wherein hydrophilic matrix refers to a uniform mixture of minocycline, hydrophilic polymers and optionally other excipients.
3. The process according to Claim 2 wherein hydrophilic polymers are cellulose derivatives.
4. The process according to Claim 3 wherein the cellulose derivative is a mixture of two different viscosity grades.
5. The process according to Claim 3 or 4 wherein cellulose derivatives may be selected from hydroxypropylcellulose, hydroxypropylmethylcellulbse, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose or combinations thereof.
6. The process according to Claim 5 wherein the cellulose derivative is hydroxypropyl methylcellulose.
7. The process according to Claim 5 wherein the cellulose derivative is hydroxypropyl cellulose.
8. The process according to Claim 6 wherein the cellulose derivative is a mixture of low viscosity and medium viscosity grades of hydroxypropyl methylcellulose.
9. The process according to Claim 7 wherein the cellulose derivative is a mixture of low viscosity and medium viscosity grades of hydroxypropyl cellulose.
10. The process according to Claim 2 wherein the concentration of the hydrophilic polymers ranges from about 5.0 to about 25 weight percent of the total composition.
11. The process according to Claim 1 wherein the minocycline non-toxic acid addition salt is hydrochloride.
12. The process according to claim 2 wherein the hydrophilic matrix contains other excipients in addition to minocycline and hydrophilic polymers.
13. The process according to claim 12 wherein other excipients are selected from diluents, binders, lubricants, glidants, disintegrants, colorants and flavoring agents.
14. The process according to Claim 1 or 2 wherein the matrix is prepared by dry blending, wet granulation, compaction or fluid bed granulation.
15. The process according to Claim 14 wherein the matrix is prepared by dry blending.
16. The process according to Claim 14 wherein the matrix is prepared by wet granulation.
17. The process according to Claim 14 wherein the matrix is prepared by compaction.
18. The process according to Claim 14 wherein the matrix is prepared by fluid bed granulation.
19. The process according to Claim 1 wherein the composition is in the form of pellets, beads, granules, tablets or pills.
20. The process according to Claim 19 wherein the composition is in the form of a tablet.
21. The process according to Claim 20 wherein the tablet is prepared by direct compression, wet granulation or compaction.
22. The process according to Claim 20 wherein the tablet is given a coating.
23. The process according to Claim 22 wherein the coating is non-functional, or rate controlling.
24. The process according to Claim 23 wherein the coating is non-functional.
25. The process according to Claim 23 wherein the coating is enteric.
26. The process according to Claim 22 wherein the coating comprises film forming polymers.
27. The process according to Claim 26 wherein film forming polymers are selected from cellulose ether or acrylic polymer or mixtures thereof.
28. The process according to Claim 27 wherein cellulose ether is hydroxypropyl cellulose or hydroxypropyl methylcellulose or mixtures thereof.
29. The process according to Claim 1 wherein the pharmaceutical composition has area-under-the-curve (AUC) comparable to the area-under-the-curve (AUC) of twice-daily immediate release dosage form.
30. A process for preparing hydrophilic matrix formulation comprising minocycline and mixture of low and medium viscosity grades of hydroxypropyl methylcellulose wherein area-under-the-curve (AUC) of once-daily tablet is comparable to AUC of twice-daily immediate release dosage form.