WO1996012477A1

WO1996012477A1 - Controlled release oral delivery system containing oxybutynin

Info

Publication number: WO1996012477A1
Application number: PCT/FI1994/000474
Authority: WO
Inventors: Pertti Rantala
Original assignee: Leiras Oy
Priority date: 1994-10-21
Filing date: 1994-10-21
Publication date: 1996-05-02
Also published as: AU7994694A

Abstract

The present invention concerns a controlled release drug delivery system for oxybutynin, its manufacture and use. The drug delivery system comprises oxybutynin in combination with a controlled release excipient comprising about 20 to 60 % by weight of a hydrophilic material comprising a heteropolysaccharide and a homopolysaccharide, in a ratio of 1:3 to 3:1, a cationic crosslinking agent for the said hydrophilic material, in an amount of 1 to 20 % by weight, and 20-79 % by weight of an inert filler.

Description

I

Controlled release oral delivery system containing oxybutyni n.

The present invention relates to controlled or extended release delivery systems for the treatment of disorders responsive to the action of an antispasmodically active agents, especially for the treatment of a neurogenic bladder, a method of preparation of the delivery systems as well as method of using them.

Oxybutynin and its salts, in particular the hydrochloride (hereinafter oxybutynin) is a musculotropic antispasmodic drug with moderate anticholinergic, systemic analgesic and local anaesthetic action. Its relaxant effect on smooth muscle is based on antagonism of a process distal to the neuromuscular junction (papaverine-like effect) and on anticholinergic action on the blockage of muscari- ne-type receptors. Oxybutynin chloride has been in clini¬ cal use for twenty years and it is indicated for the re¬ lief of symptoms associated with voiding in patients with an uninhibited neurogenic and reflex neurogenic bladder. It is also used to suppress gastric acid secretion, to relieve post-transurethral vesical pain and spasm in the gastrointestinal tract, to control detrusor dysfunction and to facilitate catheterization of the urinary bladder in myelomeningocele patients. The drug is effective when given orally.

Chemically, oxybutynin hydrochloride (DL-racemic form of 4-diethylamino-2-butynyl-phenyl-cyclohexylglycolate hy- drochloride) is a tertiary amine. It is rapidly absorbed from the gastrointestinal tract following oral admini¬ stration and its pharmacological action starts within one hour. The duration of action of the drug is three to six hours.

It has been established that after the administration of oxybutynin hydrochloride (5 mg dose tablet) , the maximum concentration of unmetabolized oxybutynin in plasma was reached within 1 h, and the elimination half-life was about 2.5 h. Due to the relatively rapid elimination of the active agent from the blood, conventional treatment with oxybutynin has comprised administering oxybutynin in a dose of 5 mg (calculated as the hydrochloride) twice or three times daily, the recommended maximal dose of oxybutynin being 20 mg per day.

In conventional treatment, the administration of oxybuty- nin is accompanied by a high initial peak concentration in the blood with associated side effects. Furthermore, the frequent need to administer the drug in order to maintain or restore the necessary concentration of active agent in the blood is cumbersome and consequently has a tendency to reduce patient compliance.

Consequently, there is a need for an oxybutynin prepara¬ tion with a sustained action. Especially there is a need for a preparation which allows for a reduction of the peak initial drug concentration in the blood and which provides for an even and substantially extended effect. Such a preparation would readily allow for a once-a-day treatment with a single oral dose.

According to the invention the afore mentioned aim has been reached by combining oxybutynin or a pharmaceutical¬ ly acceptable salt thereof, with an excipient allowing the controlled and extended, even release of the active agent over a period of time exceeding 24 hours while si- ultaneously reducing the initial peak concentrations of active agent in the blood of the patient.

Thus the invention provides a controlled release oral delivery system for the treatment of disorders responsive to the action of an antispasmodically active agent, comp¬ rising

- a therapeutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof,

- a controlled release excipient comprising

- about 20 to 60 % by weight of a hydrophilic material comprising a heteropolysaccharide and a homopo- lysaccharide, in a ratio of about 1:3 to 3:1,

- a cationic crosslinking agent for the said hydrophilic material, in an amount of about 1 to 20 % by weight,

- about 20 - 79 % by weight of an inert filler, the ratio of oxybutynin to hydrophilic material being from about 1:2 to 1:25.

The excipient used in the composition according to the invention thus comprises as one component a hydrophilic material or gelling system comprising on the hand a hete¬ ropolysaccharide, and on the other hand a homopolysaccha¬ ride which is capable of crosslinking the heteropolysac¬ charide in an aqueous fluid, such as in a gastric fluid, the ratio between the two types of saccharides being from about 3:1 to 1:3.

The heteropolysaccharide is a water soluble saccharide containing two or more kinds of sugar units, and it has excellent swelling properties. According to a preferred embodiment it comprises a xanthan gum, or a derivative thereof. Such derivatives are deacylated xanthan gum, the carboxymethyl ether and propylene glycol ester.

In the preferred embodiment, the homopolysaccharide comp- rises one or more galactomannans, and especially galacto- mannas with a higher ratio of mannose to galactose, e.g. locust bean gum. Other polysaccharides are e.g. guar gum and hydroxypropyl guar gum.

The ratio between heteropolysaccharide and homopolysacha- ride is preferably approximately 1:1. In addition the excipient contains an inert filler or diluent, which suitably is a monosaccharide, disaccharid or polyhydric alcohol, such as sucrose, dextrose, lacto¬ se, fructose, xylitol, sorbitol, and microcrystalline cellulose, or mixtures thereof.

The excipient used in the composition according to the invention contains in addition a cationic crosslinking agent which is capable of crosslinking the hydrophilic material, when this is exposed to gastrointestinal fluids, thus strengthening the gel structure and preven¬ ting an initial burst of the drug when exposed to a ga¬ strointestinal environment. The amount of cationic cross linking is at the most about 20 % by weight, such as fro bout 1 to 20, especially about 5 to 15 % by weight.

The cationic crosslinking agent can be a mono- or multi- valent salt, preferably an inorganic salt such as alkali and/or alkaline earth metal salt, such as sodium, potassium, litiu , calcium, magnesium chloride, bromide, sulfate, borate, citrate, acetate, lactate, carbonate, bicarbonate. The cationic crosslinking agent is prefera¬ bly divalent, such as in calcium sulfate, or it is sodiu chloride.

Controlled release excipients containing a combination o hetero- and homopolysaccharides as defined above with inert diluents, have been described in the US patents 4,994,276, 5,128,143, and 4,135,757.

In a preferred embodiment the excipient contains about 2 to 50, especially about 25 to 35 % by weight of the hyd¬ rophilic material or gelling system, about 5 to 15 % by weight of cationic crosslinking agents, and about 35 to 70, especially about 50 to 70 % by weight of inert di¬ luent. The ratio of oxybutynin (calculated as its hydrochloride) to hydrophilic material is preferably about 1:5 to 1:15. A suitable amount of oxybutynin in a single dose, such as in a tablet, is about 5 to 20 mg, especially about 10 mg. A suitable daily dose of opxybutynin is from about 0.05 to 0.25 mg/kg body weight, especially appr. 0.12 mg/kg body weight.

The drug delivery system according to the invention can be made by first dry blending the ingredients for the excipient, and then granulating the mixture in the pre¬ sence of small amount of fluid, such as water. The ob¬ tained granulate is therafter combined with the active ingredient for example by simple dry-blending, or by using wet granulation techniques, using e.g. water as the granulating fluid.

According to an embodiment of the invention, a suitable lubricant, known per se, can be added to the excipient and drug components to be combined. The choice of lubri¬ cants is well known in the art, and magnesium, calcium and sodium stearate may be mentioned. A suitable amount of lubricant is appr. 0,5 to 3 % by weight.

The drug-excipient mixture prepared may be compressed to tablets according to conventional tablet formation tech¬ niques. The blend may also be used as pellets, as a gra¬ nulate or powder, or filled in capsules. The dosage for¬ med obtained may be coated using any suitable coating system. Such coating systems and coating techniques are well known in the art.

According to the invention it is possible to add to the composition further agents and additives, e.g. hydropho- bic agents for regulating the hydration of the product, for example by including polymeric cellulose derivatives, such as alkyl celluloses, polymeric acrylic and methacry- lie acid derivatives, waxes, oils etc. usually in amounts amounting to about 1 to 20 % by weight. Such an addition replaces part of the inert diluent. The hydrophobic agents are as such well known in the art, and a number of them are commercially available. It is also possible to add release rate decreasing substances to the mixture of drug and excipient, for example microcrystalline cellulo¬ se in an amount of about 1 to 10 % by weight.

The present invention also concerns a method for treating a subject of a condition responsive to the action of an antispasmodically active agent, such as voiding resulting from uninhibited or reflex neurogenic bladder, gastric acid secretion, vesical pain, gastrointestinal tract spasm and detruson dysfunction, especially of neurogenic bladder, the method comprising administering to the sub¬ ject for oral ingestion a delivery system, especially a tablet, according to the invention as defined above.

The invention also concerns a method of maintaining, in a human subject, a therapeutically sufficient blood level concentration of oxybutynin or of an active metabolite thereof, such as N-desethyl oxybutynin, for an extended period of time, the method comprising administering oral- ly to the said subject a controlled release delivery sys¬ tem according to the invention, as defined above, espe¬ cially a tablet containing 5 to 20 mg of oxybutynin. Pre¬ ferably a therapeutically sufficient blood level concent¬ ration is maintained for at least about 24 hours after administration of a single dose of oxybutynin, such as a single dose of about 0.05 mg/kg to 0.25 mg/kg, especially about 0.12 mg/kg body weight, of oxybutynin or a salt thereof, e.g. the hydrochloride. The administration of a daily single dose of a 10 mg controlled release oxybuty- nin tablet gave blood level concentrations of oxybutynin of at least about 0.5 ng/ml, such as 0.5 to 2.0 ng/ml for a period of at least about 24 hours, the value following the peak value being in the area of about 0.5 to 1.0 ng/ml, as is evident from the test report.

The following examples illustrate the invention, however, without limiting the scope thereof. Parts and percentages are by weight, unless otherwise stated.

Examples 1 - 2:

In Examples 1-2, controlled release excipients in accor¬ dance with the present invention were first prepared, the oxybutynin being added subsequently, and the final mixtu¬ re then being tableted.

The excipient was prepared by dry blending the requisite amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose in a high speed mixer/granulater for 2 minu¬ tes. While running choppers/impellers, the requisite amount of water was added to the dry blended mixture, and granulated for another 2 minutes. The granulation was then dried in a fluid bed dryer to a LOD (loss on drying) of less than about 10% by weight (e.g. 4-7% LOD) . The granulation was then milled using 20 mesh screens. The ingredients of the granulations of Examples 1-2 are set forth in Table 1 below:

TABLE 1

Preparation of sustained-release excipient

Component % - Ex. 1 % - Ex. 2

1. Xanthan Gum 25 25

2. Locust Bean Gum 25 25

3. Dextrose 40 30

4. Calcium Sulfate 10 20

5. Water 10* 10*

♦Removed during processing. Next, the excipient prepared as detailed above was dry blended with the desired amount of oxybutynin HCl in a V- blender for 10 minutes. A suitable tableting lubricant (Pruv®, sodium stearyl fumarate, NF, commercially availa- ble from the Edward Mendell Co., Inc) was added, and the mixture was blended for another 5 minutes. This final mixture was compressed into tablets. The ingredients of the tablets of Examples 1-2 are set forth in Table 2 be¬ low:

TABLE 2

Tablet formulation - Examples 1-2

Component % - EX. 1 % - EX. 2

1. Excipient 93.8 93.8

2. Oxybutynin HCl 4.7 4.7

3. Sodium stearyl fumarate 1.5 1.5

Tablet weight (mg) 213.2 213.2 Hardness (Kp) 3.3 1.4

Examples 3-4:

In Examples 3-4, a controlled release excipient was pre¬ pared in accordance with the procedures set forth for Examples 1-2. The ingredients of the sustained release matrix of Examples 3-4 are set forth in Table 3 below:

TABLE 3

Component ml - Ex. 3 % " - EX. 4

1. Xanthan Gum 15 15

2. Locust bean Gum 15 15

3. Dextrose 60 60

4. Calcium Sulfate 10 10

5. Water 10* 10*

*Revomed during prosessing. Thereafter, oxybutynin tablets were prepared in accordan¬ ce with the procedure set forth in Examples 1-2. The in¬ gredients of the tablets of Examples 3-4 are set forth in Table 4 below:

TABLE 4

Component % - Ex X. 3 % - - Ex. 4

1. Excipient 95.7 93.0 2. Oxybutynin HCl 2.9 5.6

3. Sodium stearyl fumarate 1.4 1.4

Tablet weight (mg) 348.3 179.3 Hardness (Kp) 10.4 3.3

In Example 3, the drug:gel ratio is about 1:10. In Example 4, the drug:gel ratio is about 1:5. By "gel" it is meant the combined weight of xanthan gum and locust bean gum.

TEST REPORT

A bioequivalence study was carried out to assess the bio¬ availability of oxybutynin from a delivery system accor- ding to the invention, using as a reference system an ordinary 5 mg oxybutynin chloride containing tablet, af¬ ter a single peroral dose of 10 mg of oxybutynin chlori¬ de.

The study was performed as a balanced, randomized, three- period cross-over study on 24 healthy volunteers.

Pharmacokinetics

From serum concentrations of oxybutynin and its metabolite N-desethyl oxybutynin the following pharmacokinetic parameters were calculated:

AUCo., using the linear trapezoidal rule (t was the last detectable concentration) . ^{c an<} t-_nx were used as measured

The individual and mean serum time-concentration curves for both oxybutynin and its metabolite N-desethyl oxybu- tynin were provided.

The pharmacokinetic parameters were calculated and curves created using the Siphar program.

Fourteen (14) blood samples (10 ml each) were taken du¬ ring each study period according to the following schedu¬ le: 0 (pre-drug) , 0.25 (15 min) , 0.5 (30 min) , 0.75 (45 min) , 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0 and 24.0 hours following drug administration. A total of 420 ml blood was taken over the three study phases, exclusive of pre- and post-clinical blood work (30 ml) . All urine excreted during 24 h after administration of the drug was collected as follows: one sample was taken before administration (blank sample) ; thereafter, samples in fractions of four hours up to 12.0 h after administra- tion (0.0-4.0 h, 4.0-8.0 h and 8.0-12.0 h) , and in a fraction of twelve hours up to 24.0 h (12.0-24.0 h) .

Urine fractions were measured by volume, and aliquots of 2-3 ml separated into duplicate polypropylene tubes, fro- zen immediately and stored at -20°C for later examinati¬ on.

Evaluations

The data from this study was analyzed by comparing the pharmacokinetic parameters calculated for the controlled release tablet (test preparation) to those for the ordinary tablet (reference preparation) .

Analytical methods

Analysis of oxybutynin and its metabolite N-desethyl oxy¬ butynin in serum were carried out by a capillary gas chromatographic method using mass selective detector. The quantification limit of the method was 0.2 ng/ml for un¬ changed oxybutynin and 2.5 ng/ml for the metabolite. The method is linear from 0.2 ng/ml to 30 ng/ml for oxy¬ butynin and from 2.5 to 150 ng/ml for N-desethyl oxy¬ butynin, respectively.

Results

There were no statistically significant differences in the extent of oxybutynin in serum after administration of the controlled release tablet (Md AUC^---- 17.02 ng/ml*h) compared to that after intake of two 5 mg ordinary tab¬ lets (the reference preparation, Md AUCo._t= 15.86 ng/ml*h) . The peak serum concentration of oxybutynin after the test controlled release tablet (Md C,^- 2.13 ng/ml) was howe¬ ver significantly lower and it was reached significantly later (Md t_^ ^8*- 1.5 h) than those after administration of the reference tablets (Md C^- 6.86 ng/ml, Md t_miX= 0.75 h) . This is also shown in the appended Figures 1 and 2. In these Figures, Fig. 1 shows the mean serum concentra¬ tion of oxybutynin as a function of time after adminis- tartion of a 10 mg controlled release tablet of the in- vention, and 2 * 5 mg conventional tablets. Fig. 2 shows the serum concentration of the metabolite, N-desethyl oxybutynin after the said administration.

The clinical importance of the extended release pattern of the controlled release tablet was demonstrated by sta¬ tistically significantly less anticholinergic side-ef¬ fects compared to the conventional tablet. Furthermore, the high and persistent levels of the active metabolite of oxybutynin for the whole 24 h study period reflects the extended release characteristics of the 10 mg cont¬ rolled release tablet.

In summary,

1. The controlled release tablet of the invention gave a reliable pharmacokinetic profile of an extended release formulation covering the 24-hour study period.

2. There were no statistically significant differences in the AUC of oxybutynin in serum after administration of the test controlled release tablet compared to that after intake of two 5 mg ordinary tablets.

3. The controlled release tablet can be considered a suc¬ cessful and clinically bioequivalent formulation when lower peak concentrations of oxybutynin in serum are de¬ sirable to diminish anticholinergic side-effects of oxy¬ butynin.

Claims

Claims :

1. A controlled release oral delivery system for the treatment of disorders responsive to the action of an antispasmodically active agent, comprising

- a controlled release excipient comprising

- about 20 to 60 % by weight of a hydrophilic material comprising a heteropolysaccharide and a homopo¬ lysaccharide, in a ratio of about 1:3 to 3:1,

- a cationic crosslinking agent for the said hydrophilic material, in an amount of about 1 to 20 % by weight, - about 20 - 79 % by weight of an inert filler, the ratio of oxybutynin to hydrophilic material being from about 1:2 to 1:25.

2. The delivery system according to claim 1, wherein the the ratio of oxybutynin to hydrophilic material is about

1:5 to 1:15.

3. The delivery system according to claim 1 wherein the oxybutynin is in the form of its hydrochloride salt.

4. The delivery system according to claim 3 in the form of a tablet containing from 5 to 20 mg of oxybutynin hydrochloride.

5. The delivery system according to claim 3 in the form of a tablet containing about 10 mg of oxybutynin hyd¬ rochloride.

6. A method of making a controlled release oral delivery system for the treatment of disorders responsive to the action of an antispasmodically active agent, comprising providing a controlled release excipient by combining - about 15 to 60 % by weight of a hydrophilic mate rial comprising a heteropolysaccharide and a homopolysac charide, in a ratio of about 1:3 to 3:1, with

- a cationic crosslinking agent for the said hyd- rophilic material, in an amount of about 1 to 20 % by weight, and with

- about 20 - 79 % by weight of an inert filler, combining said obtained controlled release excipient wit oxybutynin, or a pharmaceutically acceptable salt thereo in an amount as to provide a ratio of oxybutynin to hyd¬ rophilic material from about 1:2 to 1:25, and, optionall using pharmaceutically acceptable adjuvants, forming the obtained mixture into a solid dosage form.

7. The method according to claim 6, wherein oxybutinin i used as its hydrochloride salt, the ratio of oxybutynin to hydrophilic material being about 1:5 to 1:15.

8. The method according to claim 7 wherein the mixture i compressed into tablets each containing from 5 to 20 mg, advantageously about 10 mg of oxybutynin hydrochloride.

9. Use of oxybutynin or its pharmaceutically acceptable salt for the preparation of an oral drug delivery system according to claim 1, providing extended and even relea¬ se of the active agent over a period of time of at least 24 hours, for the treatment of disorders responsive to the effect of an antispasmodically active agent.

10. Use oxybutynin or its salt according to claim 9 for the preparation of a drug delivery system for the treat¬ ment of a neurogenic bladder.

11. A method for treating a subject for relief of a con- dition responsive to the action of an antispasmodically active agent, the method comprising administering to the subject for oral ingestion a delivery system comprising: - a pharmaceutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof,

- a controlled release excipient comprising

- a cationic crosslinking agent for the said hydrophilic material, in an amount of about l to 20 % by weight, - about 20 - 79 % by weight of an inert filler, the ratio of oxybutynin to hydrophilic material being from about 1:2 to about 1:25.

12. The method according to claim 11 wherein the condi- tion to be treated is selected from the group consisting of voiding resulting from uninhibited or reflex neuro¬ genic bladder, gastric acid secretion, vesical pain, ga¬ strointestinal tract spasm and detruson dysfunction.

13. The method according to claim 12, wherein the condi¬ tion to be treated is neurogenic bladder.

14. The method according to claim 11, wherein the delive¬ ry system is a tablet containing from about 5 to 20 mg of oxybutynin hydrochloride.

15. The method according to claim 11 wherein oxybutynin hydrochloride is adminstered once-a-day in a single dose containing about 0.05 mg/kg to 0.25 mg/kg, especially about 0.12 mg/kg body weight of oxybutynin hydrochloride.

16. A method for maintaining a therapeutically suffi¬ ciently high blood level concentration of oxybutynin or of an active metabolite thereof, in a human subject, for an extended period of time, the method comprising ad¬ ministering orally to the subject a delivery system comprising: - a pharmaceutically effective amount of oxybutynin, or a pharmaceutically acceptable salt thereof,

- a controlled release excipient comprising

- a cationic crosslinking agent for the said hydrophilic material, in an amount of about 1 to 20 % by weight, - about 20 - 79 % by weight of an inert filler, the ratio of oxybutynin to hydrophilic material being from about 1:2 to about 1:25.

17. The method according to claim 16 wherein the extended period of time is at least about 24 hours.

18. The method according to claim 16 or 17 wherein oxybu¬ tynin hydrochloride ia administered once-a-day in a sin¬ gle dose containing about 0.05 mg/kg to 0.25 mg/kg, espe- cially about 0.12 mg/kg body weight of oxybutynin hyd¬ rochloride.