# Patent

## Title
Tannate compositions, methods of making and methods of use

## Abstract

Tannate compositions containing active pharmaceutical ingredients to be used for treating nausea, vomiting, pain, convulsions, and insomnia and manufacturing processes for preparing the tannate compositions.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a divisional of and claims priority to U.S. patent application Ser. No. 11/501,649, filed on Aug. 9, 2006, now issued as U.S. Pat. No. 8,012,506, which is a continuation-in-part of U.S. patent application Ser. No. 10/921,438, filed on Aug. 19, 2004, now issued as U.S. Pat. No. 7,094,429, which is a continuation of U.S. patent application Ser. No. 10/119,285 filed Apr. 9, 2002, U.S. Pat. No. 6,869,618, which claims the benefit of U.S. Provisional Patent. Application Ser. No. 60/282,969, filed on Apr. 10, 2001; and U.S. patent application Ser. No. 10/269,027, filed on Oct. 10, 2002, now issued as U.S. Pat. No. 7,273,623, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/328,990, filed on Oct. 12, 2001.


FIELD OF THE INVENTION
The invention relates to tannate compositions containing active pharmaceutical ingredients selected from the following therapeutic classes: antinausea, antiemetic, antiinsomnia, analgesics and anticonvulsives. The invention also relates to methods of making the above tannate compositions and methods of use.
BACKGROUND OF THE INVENTION
The use of tannate salts of active pharmaceutical ingredients is well known. U.S. Pat. No. 6,287,597 describes tannate products containing pyrilamine tannate and phenylephrine tannate. The January 1990 issue of Annals of Allergy, Volume 64, describes combinations of chlorpheniramine tannate, pyrilamine tannate and phenylephrine tannate. An article in Clinical Medicine, dated September 1965, pages 1475-1478, describes tablets of pyrilamine tannate, chlorpheniramine tannate and amphetamine tannate. Phenylephrine tannate compositions are disclosed in U.S. Pat. No. 5,599,846 and phenylephrine tannate and chlorpheniramine tannate compositions are disclosed in U.S. Pat. No. 6,037,358. None of these references describe the problems with tannate pharmaceutical products caused by the large size of the tannate molecule. Because of its size, the percentage of active free base within the tannate salt is significantly lower than that in other salt forms such as the hydrochloride or maleate. The presence of low active percentages and the variable purity of the commercially available tannate salts leads to the stoichiometry of the active free base to tannic acid in the tannate salts to vary from batch to batch. This problem was noted in U.S. Pat. Nos. 5,599,846 and 5,663,415. This causes significant processing problems during manufacture and increases the likelihood that commercially available pharmaceutical products contain variable and in some instances, sub-therapeutic levels of the active drug substances creating dosing problems. None of these references suggest or describe pharmaceutical compositions containing tannate salts of active ingredients that are prepared with reduced variability in active drug content and increased certainty that the active drug is delivered within the therapeutic range. Also, none of the references suggest or describe tannate pharmaceutical compositions in the therapeutic classes of active ingredients for antinausea, antiemetic, antiinsomnia, analgesics, or anticonvulsives.
None of the references discussed above suggest or describe the production of a tannate composition by means of an in-situ conversion of the active ingredient to the tannate salt in the presence of a dispersing agent using the method described herein to provide a dosage form which affords a sustained release of the active ingredient over prolonged intervals of time. Since the prolonged drug release character of the tannate salt enables the development of less frequent dosing regimens, such a composition is needed to improve patient compliance with dosage requirements.
SUMMARY OF THE INVENTION
The present invention relates to therapeutic compositions for symptomatic treatment of nausea, vomiting, insomnia, pain and convulsions in a warm-blooded animal where that composition comprises a pharmaceutically effective amount of an active pharmaceutical ingredient in each category as a tannate of consistent purity.
The present invention also relates to therapeutic compositions comprising a pharmaceutically effective amount of representative active pharmaceutical ingredients as tannates for each of the above therapeutic categories combined with non-tannate forms of the active pharmaceutical ingredient to provide both immediate and sustained release characteristics in the same dosage form.
The above therapeutic compositions are incorporated into various dosage forms such as semi-solid dosage forms which include liquid suspensions and soft gelatin capsules and solid dosage forms which include capsules, chewable tablets, and tablets.
The present invention also relates to a manufacturing process for in-situ conversion and incorporation thereof, of tannate salt complexes of antinausea, antiemetic, antiinsomnia, analgesic and anticonvulsive classes of pharmaceutical compounds into a sustained release therapeutic dosage form. By starting with a commonly available salt or free base of the active pharmaceutical ingredient, which is subsequently converted and incorporated in-situ as a tannate salt complex, the invention provides an efficient and reproducible method of manufacture for both solid and liquid or semi-solid products containing active ingredient tannate salt complexes.
The manufacture of tannate liquid and semi-solid dosage forms is performed according to processes described in U.S. Pat. No. 6,869,618 and U.S. Pub. No. 2005/0202050, both references are incorporated herein by reference.
The manufacture of tannate solid dosage forms is performed according to U.S. Pub. No. 2003/0077321 and U.S. Pub. No. 2005/0202080, both references are incorporated herein by reference.
The present invention also relates to methods of administering a pharmaceutically effective amount of active ingredient tannate complex of consistent purity to a warm-blooded animal.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel therapeutic composition containing a tannate salt of active ingredients of consistent purity selected from the antinausea therapeutic class. A representative active ingredient is doxylamine prepared by a tannate conversion process which includes the steps of mixing the doxylamine as a salt or in the free base form with tannic acid in a suitable solvent to generate a mixture. The mixing step is performed in the presence of a dispersing agent such as magnesium aluminum sulfate either natural or synthetic, preferably synthetic. The presence of the dispersing agent prevents the clumping and aggregation of the tannate salt formed and promotes uniformity in the mixture. Example 1, which is illustrative of a typical suspension formulation of the present invention, is prepared as follows:
Example 1










Preparation of Doxylamine Tannate Suspension













Amount



Ingredient
% W/V
(Kg)














Doxylamine Succinate
0.100%
1.7



Tannic Acid
0.325%
5.525*



Neusilin TM, UFL2
0.800%
13.600



Xanthan Gum
0.350%
5.950



Sodium Citrate Dehydrate
1.000%
17.000



Citric Acid
0.200%
3.4



Glycerin
20.000%
340.000



Saccharin Sodium
0.400%
6.800



Methylparaben
0.200%
3.400



Sodium Benzoate
0.100%
1.700



Sucrose
10.000%
170.000



Artificial Bubble Gum
1.100%
18.700



Flavor PFC9861





FD&C Blue #1
0.010%
0.170





*= Based on 100% pure, anhydrous material






Purified water, 1200 kg, is added to a 500 gallon mixing vessel. Sodium citrate dihydrate and citric acid are added to the purified water and are mixed until dissolved. The neusilin and xanthan gum are added and thoroughly dispersed. Then the tannic acid is added and thoroughly dispersed. The doxylamine succinate is then added and mixing is continued for 20-30 minutes. The sucrose and saccharin sodium are added and dispersed. The artificial bubble gum flavor and FD&C Blue #1 are added and mixed for approximately 5 minutes. After adding and dispersing the glycerin, methylparaben and sodium benzoate, the pH of the formulation is adjusted to within the range of 4.8-5.2 and the suspension is diluted to a final volume of 1700 L and mixed for 30 minutes.
Example 2










Preparation of Doxylamine Tannate Soft Gel Capsule









Ingredient
% In Total W/V
Amount (g)












Doxylamine Succinate
26.67
400.00


Tannic Acid, USP
40.00
600.00


Magnesium Aluminum Silicate
6.67
100.00


Lactose
20.0
300.00


Purified Water, USP
6.67
100.00


Totals
100.00
1500.00









The tannic acid, doxylamine succinate, magnesium aluminum silicate and lactose powders were mixed for a period of 10 minutes in a planetary mixer to obtain a uniform blend. While continuing to mix, 150 mL of purified water was sprayed onto the dry powder blend. The conversion process occurred as soon as the tannic acid and API salts were moistened. Mixing was continued for an additional 20 minutes. At this point, the conversion product had a dough-like consistency, but was still able to be poured from the bowl. The wet mass material was incorporated into soft gelatin capsules using techniques known in the art.
A non-exclusive list of other antinausea therapeutic agents that can be used in the above Examples are: proclorperazine, promethazine HCl, metochlopromide HCl, trimethobenzamide HCl, and ondansetron HCl.
Example 3










Preparation of Promethazine Tannate Suspension













Total weight



Raw Material
% in total
Reqd. (g)














Promethazine HCl, USP
0.50%
50.000



Tannic Acid, USP
0.50%
50.000



Neusilin Grade UFL2
0.80%
80.0000



Sodium Citrate Dihydrate, USP
1.90%
190.0000



Aspartame
0.20%
20.0000



Acesulfame K
0.20%
20.0000



Glycerin, USP
20.00%
2000.0000



Citric Acid, Anhydrous, USP
1.15%
115.0000



Methylparaben, NF
0.20%
20.0000



Sodium Benzoate, NF
0.10%
10.0000



Xanthan Gum
0.45%
45.0000



Strawberry Flavor
0.40%
40.0000



FD&C Red #40
0.040%
4.0000



Purified Water, USP
74.06%
7406.0000



Total
100.00%
10000.0









Promethazine HCl is dissolved in purified water. In a stainless steel mixing tank, the neusilin and tannic acid are dispersed in water using a suitable stirrer. While stirring the neusilin/tannic acid dispersion in the tank at low speed, the promethazine HCl solution is transferred in small portions to the dispersion. Stirring is continued for a minimum of 10 minutes.
In a separate mixing tank, the citric acid and sodium citrate are dissolved in purified water. The xanthan gum is slowly added and mixed until dispersed. The contents of the tank containing the active ingredient/tannic acid conversion are transferred to the xanthan gum suspending medium and mixed for a period of 10-30 minutes. The sweeteners, colors and flavors are subsequently added to the suspending medium with mixing. The sodium benzoate and methylparaben are dispersed in glycerin and subsequently added to the suspending medium and mixed to achieve a uniform dispersion. The pH is adjusted to pH 5 and purified water is added to the required volume.
A non-exclusive list of other antiemetic therapeutic agents that can be used in the above Example are: cyclizine, diphenhydramine, meclizine, chlorpromazine, droperidol, hydroxyzine, metoclopramide, proclorperazine, and trimethobenzamide, cisapride, h2-receptor antagonists, and ondansetron.
Example 4










Preparation of Hydrocodone Tannate Tablet Dosage Form









Raw Material
% W/W
Total wt (kg)












Hydrocodone Bitartrate
0.5
0.250


Tannic Acid, USP
0.5
0.250


Magnesium Aluminum Silicate, NF
8.12
4.060


Avicel PH 102
67.76
33.880


Methocel E-10M
1.40
0.700


Corn Starch
0.80
0.400


Di-Pac
12.00
6.000


Sodium Saccharin
2.00
1.000


Calcium Phosphate Dibasic
2.80
1.400


Xanthum Gum
3.00
1.500


Talc
0.56
0.280


Magnesium Stearate
0.56
0.280


Purified Water
N/A
8.5 L*


Total
100.000%






*Removed upon drying






Add the hydrocodone bitartrate, tannic acid, magnesium aluminum silicate, avicel pH102 and methocel E-10M to a small paddle blender. While mixing the powders, spray with purified water. The material should exhibit a dough-like texture when complete. Add the remaining powders and mix until uniform. If excess water is present, it may be removed by drying prior to tabletting using conventional techniques.
A non-exclusive list of other analgesics that can be used in the above Example are: codeine, diacetylmorphine, dihydrocodeine, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone and propoxyphene.
Example 5










Preparation of Diazepam Tannate Suspension











Raw Material
% W/V
mg/5 ml














Diazepam
0.100%
5



Tannic Acid
0.100%
5



Saccharin Sodium
0.300%
0.015



Sucrose
10.000%
0.500



Glycerin
7.500%
0.375



Magnesium Aluminum Silicate
0.800%
0.040



Xanthum gum
0.520%
0.026



Dibasic sodium phosphate
1.000%
1.050



Methylparaben
0.200%
0.010



Sodium benzoate
0.100%
0.005



FD&C Red No. 40
0.040%
0.002



Strawberry Flavor
0.500%
0.025



Purified Water
qs to volume
N/A









The sodium phosphate dibasic is dissolved in purified water in a suitable stainless steel mixing tank. The MAS, followed by xanthan gum, is dispersed in the solution. The coloring agent FD&C Red No. 40 and the artificial strawberry flavor are then added and mixed to generate the suspending medium. In a separate mixing tank, the MAS and tannic acid are dispersed in water using a suitable stirrer. Mixing is continued until a uniform dispersion is achieved.
Diazepam is dissolved in purified water. While stirring the MAS/tannic acid dispersion in the mixing tank at low speed, the diazepam solution is transferred in small portions to the dispersion. Stirring is continued for a minimum of 10 minutes. After mixing, the contents of the tank are transferred to the suspending medium and mixed for a period of 5 minutes.
The sodium benzoate and methylparaben are dispersed in glycerin in a mixing tank using a suitable mixer. The glycerin mixture is then added to the suspending medium and mixed to achieve a uniform dispersion. Finally, purified water is added to make up the suspension to the required volume.
A non-exclusive list of other sedatives that can be used in the above Example are: clorazepate, estazolam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, quazepam, zolpidem, zaleplon, amitriptyline, trimipramine, and trazodone.
Example 6










Preparation of Phenytoin Tannate Chewable Tablet











Ingredient
% W/V
Amount (Kg)














Phenytoin
10.00
4.840



Tannic Acid, USP
10.00
4.840



Neusilin
1.35
0.653



Mannitol
35.50
17.180



Sodium Saccharin
0.90
0.396



Corn Starch
0.90
0.446



Methocel E-10M
1.35
0.653



DiPac
48.83
21.500



Calcium Phosphate Dibasic
2.70
1.188



Xanthan Gum
1.57
0.691



Artificial Strawberry Flavor
0.90
0.396



FD&C Blue No. 1
0.09
0.040



Talc
0.45
0.198



Magnesium Stearate
0.45
0.198



Purified Water
NA
NA









The tannic acid and neusilin powders are mixed in a blender for about 10 minutes. The phenytoine is dissolved in water and sprayed onto the powders while mixing. The mannitol and sodium saccharin are added and mixed until uniform. The methocel is added and mixed until uniform. An aqueous solution of corn starch is then applied to the powders while mixing.
After drying to remove the excess water, the material is milled. The milled powder is then blended with the remaining ingredients dipac, calcium phosphate dibasic, xanthan gum, flavor, color, magnesium stearate and talc until uniform and compressed into tablets using techniques known in the art.
A non-exclusive list of other anticonvulsion therapeutic agents that can be used in the above Example are: hydantoins including mephenytoin; succimides including ethosuximide and methsuccimide; benzodiazepines, which are better known for their use as tranquilizers and sedatives, including clonazepam, clorazepate, diazepam, carbamazepine, valproic acid, gabapentin, topiramate, felbamate, and phenobarbital.
Example 7










Preparation of Dimenhydrinate Tannate and Dimenhydrinate


Non-Tannate Tablet Dosage Form









Ingredient
% In Total, w/v
Amount (g)












Dimenhydrinate
12.50%
1000.0


Tannic Acid, USP
12.50%
750.00


Magnesium Aluminum
2.00%
176.00


Silicate (MAS), NF




Methocel E-10M (HPMC)
35.88%
3157.42


Lactose
32.53%
2602.58


FD&C Blue #1 Aluminum Lake
0.30%
24.00


Colloidal Silicon Dioxide
0.50%
40.00


Magnesium Stearate, NF
1.25%
100.00


Purified Water, USP~*
NA
150.00


TOTAL
100.00%
8000.0





*An excess of 10% is added to raw materials used in the wet granulation to correct for losses.






Tablets utilizing the above formulation are prepared as follows. The tannic acid, MAS, and 3⁄4 dimenhydrinate dry powders are mixed for a period of 10 minutes in a planetary mixer to obtain a uniform blend. While continuing to mix, 150 mL of purified water is sprayed onto the dry powder blend. The conversion process occurs as soon as the tannic acid and API salts are moistened. Mixing is continued for an additional 20 minutes. At this point, the conversion product has a dough-like consistency, but is still able to be poured from the bowl.
To a separate mixing vessel, most preferably a paddle blender, the following dry powders are added: methocel E-10M (HPMC) and lactose. The conversion product is poured evenly over these dry powders, and the mixture is then blended for 20 minutes. At this point, a product resembling a typical wet granulation is obtained. The mixture is then dried and milled as needed. The remainder of the excipients and the dimenhydrinate are added and the mixture is blended for an additional 20 minutes. The final blend is then processed into tablets using techniques well known in the art.
Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

## Claims

1. A process for the conversion of at least one pharmaceutical ingredient into a tannate salt complex for incorporation into a therapeutic liquid or semi-solid dosage form, the process comprising:
(a) dissolving the salt or free base of the active pharmaceutical ingredient in a pharmaceutically acceptable liquid in the presence of a dispersing agent and tannic acid under stirring, to form a dispersion wherein the tannic acid component is of either a natural or synthetic source;
(b) combining the tannate salt complex of the active pharmaceutical ingredient without isolation or purification with pharmaceutically acceptable excipients to generate a therapeutic dosage form; wherein the active pharmaceutical ingredient is selected form the group consisting of an antinausea agent, an antiemetic, a sedative and an anticonvulsive and wherein the antinausea agent is selected from the group consisting of doxylamine, prochloroperazine, promethazine HCL, metochloropromide HCL and ondansetron HCL.

2. The process according to claim 1 wherein the dispersing agent provided in step (a) is selected from the group consisting of natural magnesium aluminum silicate and synthetic magnesium aluminum silicate.

3. The process according to claim 2 wherein the dispersing agent is synthetic magnesium aluminum silicate.

4. The process according to claim 1 wherein step (b) includes adding a non-tannate active pharmaceutical ingredient.

5. The process of claim 1 wherein the antiemetic is selected from the group consisting of: promethazine, cyclizine, diphenhydramine, meclizine, chlorpromazine, droperidol, hydroxyzine, metoclopramide, prochlorperazine, and trimethobenzamide, cisapride, h2-receptor antagonists, and ondansetron.

6. The process of claim 1 wherein the sedative is selected from the group consisting of: clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, quazepam, zolpidem, zaleplon, amitriptyline, trimipramine, and trazodone.

7. The process of claim 1 wherein the anticonvulsive is selected from the group consisting of: phenytoin, mephenytoin, ethosuximide, methsuccimide, clonazepam, clorazepate, diazepam, carbamazepine, valproic acid, gabapentin, topiramate, felbamate, and phenobarbital.

8. A process for the conversion of at least one active pharmaceutical ingredient into a tannate salt complex for incorporation into a therapeutic tablet, capsule or other solid dosage form, the process comprising mixing the salt or free base of the at least one active pharmaceutical ingredient, tannic acid, and a dispersing agent in a pharmaceutically acceptable liquid to form a tannate salt complex of the at least one pharmaceutical active ingredient for incorporating into a tablet, capsule or other dosage form; wherein the at least one pharmaceutical active ingredient is selected from the group consisting of an antinausea agent, an antiemetic, a sedative and an anticonvulsive and wherein the antinausea agent is selected from the group consisting of: doxylamine, prochlorperazine, promethazine HCl, metochlopromide HCl, trimethobenzamide HCl, and ondansetron HCl.

9. The process of claim 8 further comprising incorporating the tannate salt complex of the at least one pharmaceutical active ingredient into a tablet, capsule, or other dosage form.

10. The process according to claim 8 wherein the dispersing agent is selected from the group consisting of natural magnesium aluminum silicate and synthetic magnesium aluminum silicate.

11. The process according to claim 10 wherein the dispersing agent is synthetic magnesium aluminum silicate.

12. The process according to claim 8 further comprising adding a non-tannate active pharmaceutical ingredient.

13. The process according to claim 8 wherein the antiemetic is selected from the group consisting of: promethazine, cyclizine, diphenhydramine, meclizine, chlorpromazine, droperidol, hydroxyzine, metoclopramide, prochlorperazine, trimethobenzamide, cisapride, h2-receptor antagonists, and ondansetron.

14. The process according to claim 8 wherein the sedative is selected from the group consisting of: clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, quazepam, zolpidem, zaleplon, amitriptyline, trimipramine, and trazodone.

15. The process according to claim 8 wherein the anticonvulsive agent is selected from the group consisting of: phenytoin, mephenytoin, ethosuximide, methsuccimide, clonazepam, clorazepate, diazepam, carbamazepine, valproic acid, gabapentin, topiramate, felbamate, and phenobarbital.