WO1999043302A1

WO1999043302A1 - Stabilizing composition for pharmaceutical dosage forms

Info

Publication number: WO1999043302A1
Application number: PCT/US1999/004361
Authority: WO
Inventors: Thomas C. Ho
Original assignee: Watson Pharmaceuticals Inc
Current assignee: Allergan Finance LLC
Priority date: 1998-02-27
Filing date: 1999-02-26
Publication date: 1999-09-02
Anticipated expiration: 2000-08-27
Also published as: AU2882699A

Abstract

A new stabilizer component for incorporation into pharmaceutical dosage forms and methods of making pharmaceutical dosage forms with enhanced stability is provided. Betaine-HC1 provides enhanced stability, superior bioavailability and low toxicity in comparison with carboxylic acid compounds and other stabilizers of the prior art.

Description

STABILIZING COMPOSITION FOR PHARMACEUTICAL DOSAGE FORMS

Field of the Invention The invention relates to improved stabilizer components for inclusion in pharmaceutical dosage forms such as tablets and capsules.

Background of the Invention Pharmaceutical dosage forms commonly include one or more stabilizing constituents, to prevent dissociation or other degradation of the active agent subsequent to manufacture and prior to administration of the drug. Traditionally, various carboxylic acids such as citric acid, malic acid, cinnamic acid, glycolic acid, malonic acid, maleic acid and others have been incorporated into pharmaceutical dosage forms to increase stability and concomitant shelf life. In many instances, carboxylic acid stabilizers are satisfactory and impart adequate shelf life for tablets and capsules incorporating them along with the various active agents they are meant to stabilize.

Carboxylic acid stabilizers of the prior art do not always, however, provide optimal stability to sensitive pharmaceutically active agents, particularly those active agents which are themselves acid addition salts of various organic compounds. On the other hand, carboxylic acids are virtually always if not ubiquitously benign ingredients in pharmaceutical dosage forms because of their intrinsic biocompatibility and generally low toxicity.

Betaine and its related compounds have been used as stabilizers in a number of formulations. The use of betaine chloride in a rehydration drink to protect membranes against reduced activity resulting from dehydration is shown in United States Patent No. 5,397,786. The use of betaine as a surfactant in a mouthwash is shown in United States Patent 5,180,577. In both of these patents, however, the betaine compounds were used to impart or stabilize physical properties in a mixture or a biological system rather than to provide chemical stability. United States Patent No. 5,078,997 shows the use of betaine in a pharmaceutical composition, but the compound is used to stabilize the solubility of the formulation rather than to stabilize the chemical integrity of the active ingredient. A need therefore remains for a specialized stabilizer, for use in pharmaceutical dosage forms such as tablets and capsules, which provides enhanced product chemical stability and physical stability together with good bioco patibility and low toxicity.

Summary of the Invention

In order to meet this need, the present invention is an amino acid derivative especially well suited to stabilizing acid addition salts of pharmaceutically active agents in solid dosage forms. Specifically, the present additive is betaine-HCl, and the invention embraces both its presence in pharmaceutical dosage forms as a stabilizer in addition to methods of making pharmaceutical dosage forms having enhanced stability as a result of the incorporation of betaine-HCl. An exemplary active agent whose stability is enhanced with betaine-HCl is ticlopidine; many other acid addition salt active agents are similarly improved with the use of the stabilizing component .

The invention includes a pharmaceutical composition, a method for stabilizing a pharmaceutically active agent in a dosage form, and a method for manufacturing a pharmaceutical dosage form.

Brief Description of the Drawings FIG. 1 is a graph of plasma concentrations of ticlopidine with respect to time, after the administration of a 250 mg dose, in a comparative study of bioavailability of two ticlopidine hydrochloride formulations.

FIG. 2 is a graph of plasma concentrations of ticlopidine with respect to time, after the administration

•2- of a 250 mg dose, in a study of the effect of food on the bioavailability of ticlopidine hydrochloride.

Detailed Description of the Invention Betaine-HCl is a uniquely useful stabilizer for incorporation in pharmaceutical solid dosage forms. As an additive, betaine-HCl does not interfere with bioavailability of active agents and typically imparts improved chemical and storage stability to any one or more active agents with which it is admixed. Betaine-HCl is particularly suited as a stabilizer for admixture to acid- addition salt active agents, including but not limited to ticlopidine-HCl, tetracycline-HCl cephem carboxylic acid addition salt, thiaxanthine nuclear ester acid addition salt, phthalazinone acid addition salt, morphine acid addition salt, indenyloxymethylmorpholine acid addition salt, triphenylethylene acid addition salt, delta- aminolevulinic acid addition salt, ibuprofen acid addition salt, meglumine acid addition salt, ibopamine acid addition salt, dimethylglycine acid addition salt, bacampicillin acid addition salt, rosamicin ester acid addition salt, and hydroxybenzyl azetidine acid addition salt. From this exemplary list it is apparent that the applications for betaine-HCl as a pharmaceutical stabilizer are without limit, as the class of acid addition salts is made up of the large number of acidic ionic chemical compounds able to be formed by a basic compound in conjunction with an acid. A "stabilizing amount" is the amount of a compound required to preserve the active agent against chemical or physical degradation.

Depending of the compound to be stabilized, anywhere up to about 50% by weight betaine-HCl may be needed to provide appropriate stability to dosage forms in which it is incorporated; a range of about 0.01% by weight to about 20% by weight betaine-HCl is suitable for most compounds. Typical dosage forms as tablets or capsules would further contain about 50-70% by weight active agent, remainder excipients including but not limited to typical pharmaceutical ingredients such as corn starch, magnesium stearate, polyvinylpyrrolidone, various methyl celluloses and other known excipients, fillers, binders and tableting agents known in the pharmaceutical arts . A preferred range of inclusion of betaine-HCl in a final dosage form is about 1-5% by weight of the final product. A particularly preferred range of inclusion of betaine-HCl in a final dosage form is about 2-4% by weight of the final product. "Excipients" are inert substances forming a vehicle for a drug. These may include binders, fillers, tableting agents and other compounds having functions in a drug formulation other than those of an active ingredient. "Fillers" are substances added to a product to increase its bulk. "Binders" are substances used to hold together the ingredients of a tablet. "Tableting agents" are a type of binder specifically intended to facilitate the binding of ingredients in tablet form.

Betaine-HCl requires no particular care in handling and can be incorporated in pharmaceutical dosage forms in various ways as long as extreme conditions of heat and freezing are avoided. An exemplary formulation and manufacturing method illustrating the incorporation of betaine-HCl in ticlopidine dosage forms is shown in Table 1. The exemplary manufacturing method includes weighing ingredients, mixing the pharmaceutically active agent with one or more excipients such as starch and Avicel 101 to form a pharmaceutically active agent mixture, dissolving betaine-HCl and polyvinylpyrrolidone in water to form an aqueous solution of betaine-HCl, and adding the pharmaceutically active agent mixture to the aqueous solution of betaine-HCl to form a combined mixture. This combined mixture is then blended by an acceptable pharmaceutical manufacturing process to distribute the active agent evenly throughout the blend. Dry blending or wet blending processes may be used; a wet process known as wet granulation employs a dispersing agent such as water or

-4- alcohol for blending, followed by drying. The resulting dry granules are milled, blended with other formulating agents such as Avicel 101, stearic acid, and magnesium stearate, and the resulting blended materials are compressed into the final dosage form. In this exemplary method, Avicel 101, which is a cellulose derivative, acts as a binder and disintegrant . Corn starch acts as a binder. Polyvinylpyrrolidone (PVP) acts as a dispersion aid. Stearic acid and magnesium stearate are tableting agents. The disclosed formulation is susceptible of widespread modification, however, such as by eliminating the stearic acid, substituting sodium starch glycolate or similar compounds for the corn starch, for example, providing additional thin coatings to the final dosage form, and so forth.

Tests were conducted on a ticlopidine-HCl formulation containing betaine-HCl. Two sets of samples were exposed, over a two-year period, to temperatures between 25°C and 30°C, and to 40°C at 75% relative humidity, respectively. The ticlopidine-HCl was observed to remain stable over this period in both sets of samples .

EXAMPLE 1

A study was conducted to compare the relative bioavailability of the ticlopidine formulation of the present invention with a reference ticlopidine formulation when given after an overnight fast to healthy, adult, male subjects .

This randomized, single-dose, two-way crossover study was conducted with 29 healthy, adult, male subjects. A single 250 mg dose of ticlopidine was administered in each study period after an overnight fast. Watson Laboratories, Inc . ' s 250 mg tablets (formulated according to the present invention) were the test formulation, and 250 mg Ticlid^® (Roche Laboratories, Inc.) tablets were the reference formulation. One of the formulations was given in each period; the order of administration was determined according to the dosing randomization schedule. There was a 7 day washout between treatments. Blood samples were collected pre-dose and over 96 hours after each dose, as shown in Table 3. Plasma concentrations of ticlopidine were measured in these samples. Pharmacokinetic parameters were calculated from the data and statistical analyses were performed to compare the test and reference treatments .

Peak concentration (C_maχ) was the observed maximum value. The time to peak concentration (T_maχ) was the time at which C_maχ was observed.

The apparent first order elimination rate (K_e) was estimated as the absolute value of the slope of the regression line for the terminal log-linear concentration- time values. The values included in the regression analyses were determined by examination of the individual subject plots of natural logarithm of concentration against time. Elimination half-life (ELIMHALF) was calculated as 0.693/K_e.

Area under the curve (AUC) to the time of the last non-zero concentration (C^) was calculated by the linear trapezoid method. Area to infinite time (AUC_inf) was calculated by extrapolating AUC by the addition of the quantity C^/K_g.

Based on meeting 90% confidence interval criteria on the test-to-reference ratio for area and peak concentration (within the interval 0.80 - 1.25), the formulation of the present invention appears to be bioequivalent to the Ticlid^® reference (Table 2) .

EXAMPLE 2 A study was conducted to compare the relative bioavailability of the ticlopidine hydrochloride formulation of the present invention to a reference ticlopidine hydrochloride formulation when given under post-prandial and fasting conditions in healthy, adult, male subjects.

-6- This randomized, single-dose, three-way, crossover study was conducted with 16 healthy, adult, male subjects. A single 250 mg dose of ticlopidine was administered in each study period after an overnight fast or a standardized breakfast. Watson Laboratories, Inc.'s 250 mg tablets (formulated according to the present invention) were the test formulation and 250 mg Ticlid^® (Roche Laboratories, Inc.) tablets were the reference formulation. One of the formulations was given in each period; the order of administration was determined according to the dosing randomization schedule. There was a 7 day washout between treatments.

Blood samples were collected pre-dose and over 96 hours after each dose, as shown in Table 5, and plasma concentrations of ticlopidine were analyzed statistically for the subjects. Pharmacokinetic parameters were calculated from the data and statistical analyses were performed to compare the formulation of the present invention and reference formulation under fed and fasted conditions . Peak concentration (C_maχ) was the observed maximum value. The time to peak concentration (T_maχ) was the time at which C_max was observed.

Area under the curve (AUC) to the time of the last non-zero concentration (C-^) was calculated by the linear trapezoid method. Area to infinite time (AUC__|__nf) was calculated by extrapolating AUC by the addition of the quantity C-_j_/K_e.

It is concluded that a comparable food effect is

-7- observed since the mean value of AUC₀__t, AUC_inf and C_maχ for the formulation of the present invention (the Watson product tabulated as Test-1) and the reference formulation (Ticlid^®) are within the 20% limits of the respective mean values for Ticlid^® administered with food (Table 4) .

TICLOPIDINE-HC1 CORE TABLETS, 250 MG LOT EXP-PW-62

Ingredients % mg/tablet Lot No. Amount

Ticlopidine-HCl 62.5 250.0 XXG1296 312.5 g

Betaine HCl 3.13 12.52 XXB1697 15.65 g

Avicel 101 16.87 67.48 J6495 84.35 g

Avicel 101 10.0 40.0 J6495 50.0 g

PVP 2.0 8.0 E0396 10.0 g

Corn Starch 4.0 16.0 J18695 20.0 g

Stearic Acid 1.0 4.0 C4896 5.0 g

Mg Stearate 0.5 2.0 B6296 2.5 g

TOTAL 500.0 g

1. Weigh all ingredients

2. Pre-mix Ticlopidine + 84.35 g Avicel 101 + 20.0 g Corn Starch in Hobart Mixer with scale 1 setting for 10 minutes to form pharmaceutically active agent mixture; LOD = 1.34%

Dissolve 15.65 g Betaine HCl + PVP in 120 mL water to form Betaine HCl solution.

Combine (2) and (3) . Combined mixture is wet granulated and dried.

Granulation time: 6-7 min.

LOD: 1.21%

H₂0 used: 120 mL + 30 mL = 150 mL

Total wt . : 420.6 g

Table 1

^■9- TICLOPIDINE-HC1 CORE TABLETS, 250 MG (continued)

Time Inlet Temp. Outlet temp. Damper

10:20 82 44 25

10:21 62 36 23

10:24 54 32 23

10:27 64 30 23

10:30 62 36 23

10:33 62 40 23

10:36 60 43 23

10:40 60 48 23

5. Mill dry granules through #20 mesh screen with knive forward and middle speed setting.

6. Blend milled materials + 50.0 g Avicel 101 for 10 mins. and add stearic acid + Mg stearate blend for 5 more minutes. Total weight = 476.2 gm.

7. Compress to final dosage form:

Tooling: 0.3" x 0.6" oval shape with "WATSON" logo; total weight = 400 mg.

Friability: [ (7.2268-7.2268) 7.2268] x 100 = 0% Thickness : 0.190-0.192" Hardness : 5.6, 5.8, 8.3, 8 8, 9.1 and 9.6 Tablet weight: N 10

402.4 mg

R 397.4 407.6 mg

RSD = 0.67%

Table 1 (continued)

^• 10 - TICLOPIDINE STUDY NO. 9709890

SUMMARY TABLE

Comparisons of ticlopidine results for Watson's 250 mg tablets (Test) vs. 250 mg Ticlid^® tablets (Reference) administered under fasting conditions, N=27.

Parameter Least Squares Means ^! Test/Ref. Power ³ 90% Confidence Interval ⁴ Ratio ²

Test-1 Reference Lower Upper

AUC₀._t 2992.93 2850.74 1.050 0.99 0.972 1.127 (ng-hr/ml)

AUC_ιnf 3195.04 3088.32 1.035 0.97 0.951 1.118 (ng-hr/ml) c ^max 758.56 802.79 0.945 0.91 0.845 1.044

(ng/ml)

T ^A max 1.89 2.10 0.903 0.99 *

(hour) _e 0.0586 0.0604 0.971 0.92 (1/hour)

Elimhalf 25.76 22.22 1.159 0.30 (hour)

Ln-Transformed Data

AUC₀._t 2575.46 2428.84 1.060 0.97 0.964 1.166 (ng-hr/ml)

AUC_inf 2771.38 2742.56 1.011 0.99 0.930 1.098 (ng-hr/ml) c 684.67 699.30 0.979 0.92 0.878 1.092

(ng/ml)

1. Least squares geometric means for In-transformed data.

2. Test/Ref Ratio calculated as Test mean divided by Reference mean. 3. Power to detect a difference of 20% (original data) or a ratio of 1.25 (In-transformed data).

4. Confidence interval on the ratio.

* Detected as statistically significant by ANOVA (α = 0.05)

Table 2

- 11- TICLOPIDINE STUDY NO. 9709890

SUMMARY TABLE

Summary of ticlopidine statistical comparisons at each sampling time comparing Watson's 250 mg tablets (Test) vs. 250 mg Ticlid^® tablets (Reference) under fasting conditions, N=27.

Sample Collection Least Squares Means (ng/ml) Time (Hour)

Test Reference

1 Pre-dose 0.00 0.00

2 0.5 71.21 32.15

3 1.0 320.69 263.07

4 1.5 564.28 541.94

5 2.0 632.53 680.95

6 2.5 536.60 568.19

7 3.0 386.75 461.15

8 3.5 295.14 319.29

9 4.0 236.59 242.75

10 5.0 143.80 147.83

11 6.0 109.57 94.28

12 8.0 74.19 58.90

13 10.0 66.21 52.98

14 12.0 43.17 41.28

15 16.0 34.18 30.23

16 24.0 17.91 14.43

17 36.0 11.05 9.49

18 48.0 6.76 5.81

19 72.0 3.14 3.02

20 96.0 1.53 1.36

Table 3

^■12- TICLOPIDINE STUDY NO. 9709891

SUMMARY TABLE

Comparisons of ticlopidine results for Watson's 250 mg tablets (Test-1) vs. 250 mg Ticlid^® tablets (Reference),

N=16.

Parameter Least Squares Means ' Test Ref. Power ³ 90% Confidence Interval ⁴ Ratio ²

Test-1 Reference Lower Upper

AUC_0-t 2672.43 2551.40 1.047 0.88 0.943 1.152 (ng-hr/ml)

AUC_inf 2904.92 2968.04 0.979 0.29 0.747 1.211 (ng-hr/ml) r ^Tnax 724.05 774.24 0.935 0.79 0.816 1.054

(ng/ml)

T ⁱ max 2.01 2.07 0.971 0.43

(hour) _e 0.0329 0.0320 1.028 0.06

(1/hour)

Elimhalf 23.87 37.02 0.645 0.10 (hour)

Ln-Transformed Data

AUC_0-t 2471.70 2355.75 1.049 0.71 0.907 1.213 (ng-hr/ml)

AUC_inf 2602.56 2852.79 0.912 0.27 0.694 1.200 (ng-hr/ml) c 654.74 709.93 0.922 0.64 0.787 1.081

(ng/ml) 1. Least squares geometric means for In-transformed data.

2. Test/Ref Ratio calculated as Test mean divided by Reference mean.

3. Power to detect a difference of 20% (original data) or a ratio of 1.25 (In-transformed data).

4. Confidence interval on the ratio.

Table 4

^• 13 - TICLOPIDINE STUDY NO. 9709891 SUMMARY TABLE

Summary of ticlopidine statistical comparisons at each sampling time comparing Watson's 250 mg tablets (Test-1 and -2) vs. 250 mg Ticlid^® tablets (Reference), N=16.

Sample Collection Least Squares Means (ng ml) Time (Hour)

Test-1 Test-2 Reference

1 Pre-dose 0.00 0.00 0.00

2 0.5 29.23 77.37 8.76

3 1.0 223.67 299.02 150.90

4 1.5 507.92 437.83 438.44

5 2.0 534.86 414.03 533.56

6 2.5 444.15 369.26 560.04

7 3.0 381.68 319.69 450.84

8 3.5 299.99 280.67 350.91

9 4.0 261.21 195.90 272.74

10 5.0 150.02 107.48 151.75

11 6.0 92.16 80.35 89.35

12 8.0 56.91 47.73 55.78

13 10.0 45.05 40.43 44.55

14 12.0 36.64 36.89 32.86

15 16.0 26.16 23.99 21.94

16 24.0 19.17 15.36 13.04

17 36.0 12.26 7.94 9.73

18 48.0 5.40 5.00 5.44

19 72.0 2.91 2.47 2.39

20 96.0 1.97 1.06 1.25

Table 5

-14-

Claims

I claim :

1. A pharmaceutical dosage form comprising at least one pharmaceutically active agent, at least one pharmaceutically acceptable excipient, and a stabilizing amount of betaine-HCl, in combination in a solid unit dosage form.

2. The pharmaceutical dosage form of claim 1 wherein the pharmaceutically active agent is an acid addition salt.

3. The pharmaceutical dosage form of claim 1 wherein the pharmaceutically active agent is selected from the group consisting of ticlopidine-HCl, tetracycline-HCl cephem carboxylic acid addition salt, thiaxanthine nuclear ester acid addition salt, phthalazinone acid addition salt, morphine acid addition salt, indenyloxymethyl- morpholine acid addition salt, triphenylethylene acid addition salt, delta-aminolevulinic acid addition salt, ibuprofen acid addition salt, meglumine acid addition salt, ibopamine acid addition salt, dimethylglycine acid addition salt, bacampicillin acid addition salt, rosamicin ester acid addition salt, and hydroxybenzyl azetidine acid addition salt.

4. The pharmaceutical dosage form of claim 1 wherein the betaine-HCl is present at a concentration up to and including about 50% by weight.

5. The pharmaceutical dosage form of claim 1 wherein the betaine-HCl is present at a concentration between about 0.01% and about 20% by weight.

6. The pharmaceutical dosage form of claim 5 wherein the betaine-HCl is present at a concentration between about 1% and about 5% by weight.

ΓÇó15-

7. The pharmaceutical dosage form of claim 6 wherein the betaine-HCl is present at a concentration between about 2% and about 4% by weight.

8. The pharmaceutical dosage form of claim 1 wherein the pharmaceutically active agent is present at a concentration between about 50% and about 70%.

9. A pharmaceutical dosage form comprising: ticlopidine-HCl in the amount of about 62%; betaine-HCl in the amount of about 3%; and excipients in the remaining amount; in a solid unit dosage form.

10. A pharmaceutical dosage form according to claim 9 in which the excipients further comprise:

Avicel 101 in the amount of about 27%; PVP in the amount of about 2%; corn starch in the amount of about 4%; stearic acid in the amount of about 1%; and magnesium stearate in the amount of about 0.5%.

11. A method for stabilizing at least one pharmaceutically active agent in a pharmaceutical dosage form which comprises combining the pharmaceutically active agent with betaine-HCl during preparation of a solid dosage form containing said pharmaceutically active agent.

12. The method of claim 11, wherein the pharmaceutically active agent is an acid addition salt.

13. The method of claim 11, wherein the pharmaceutically active agent is selected from the group consisting of ticlopidine-HCl, tetracycline-HCl cephem carboxylic acid addition salt, thiaxanthine nuclear ester acid addition salt, phthalazinone acid addition salt, morphine acid addition salt, indenyloxymethylmorpholine

^Γûá16- acid addition salt, triphenylethylene acid addition salt, delta-aminolevulinic acid addition salt, ibuprofen acid addition salt, meglumine acid addition salt, ibopamine acid addition salt, dimethylglycine acid addition salt, bacampicillin acid addition salt, rosamicin ester acid addition salt, and hydroxybenzyl azetidine acid addition salt .

14. The method of claim 11, wherein the betaine-HCl is incorporated into said dosage form at a concentration up to and including about 50% by weight.

15. The method of claim 14, wherein the betaine-HCl is incorporated at a concentration between about 0.01% and about 20% by weight.

16. The method of claim 15, wherein the betaine-HCl is incorporated at a concentration between about 1% and about 5% by weight.

17. The method of claim 16, wherein the betaine-HCl is incorporated at a concentration between about 2% and about 4% by weight.

18. The method of claim 11, wherein the pharmaceutically active agent is incorporated into said dosage form at a concentration between about 50% and about 70%.

19. A method for manufacturing a pharmaceutical dosage form, comprising: mixing the pharmaceutically active agent with at least one ingredient selected from the group consisting of excipients, fillers, binders and tableting agents to form a pharmaceutically active agent mixture; dissolving betaine-HCl, and at least one ingredient selected from the group consisting of excipients, fillers,

ΓÇó17- binders and tableting agents, in water to form a betaine- HCl solution; combining the pharmaceutically active agent mixture and the betaine-HCl solution to form a combined mixture; blending and forming dry granules from the combined mixture ; milling the dry granules to form milled material; blending the milled material; and compressing the milled material to produce a solid dosage form.

20. The method of claim 19, further comprising providing at least one thin coating to said solid dosage form.

-18-