HK1060691B - Ion-strength independent sustained release pharmaceutical formulation - Google Patents

Description

Sustained release pharmaceutical preparation unaffected by ionic strength

The present invention relates to a pharmaceutical preparation having substantially an extended release profile independent of the ionic strength of the dissolution medium, such as the digestive juices of the gastrointestinal tract. The extended release may be for a period of up to sixteen hours. The dosage form combines a mixture of one or more active substances and a hydrophilic polymer carrier, resulting in a gel-forming matrix formulation.

Hydrophilic gel forming matrix formulations are well known dosage forms that control the dissolution behavior of active substances. The active agent releasing mechanism begins with the hydration of the surface of the dosage form to form a gel structure. At the same time, the surface active substance of the preparation is dissolved in the dissolving medium. At the stationary phase, the dissolution medium continuously penetrates the gel structure to swell the gel. The active substance dissolves in the dissolution medium and is transported to the outer layer of the gel. With erosion of the outer layer of the gel. Finally, the extent of release is reduced by the reduction of the concentration gradient of the active substance in the formulation and by the penetration of the dissolution medium. This mechanism belongs to the prior art such as manford robinson, chapter fourteenth of second edition of industrial pharmaceutical theory and practice: [ sustained action dosage form](TheTheory and Practice of industrial Pharmacy，2^nd edition，Chapter 14：“Sustained Action Dosage Forms”)。

The hydrophilic polymers used in the aforementioned formulations are mostly polysaccharide carriers such as cellulose derivatives, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), Hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (NaCMC), or combinations of these cellulose derivatives.

These types of formulations are described in ｃA number of patents and patent applications such as US 4,871,548 and EP-A-0923934.

US 4,871,548 discloses a controlled release dosage form comprising an active compound and a mixture of at least one low viscosity cellulose ether and one high viscosity cellulose ether. EP-A-0923934 discloses modified release matrix formulations of cefaclor (cefaclor) and cephalexin (cephalexin) comprising 5-35% of ｃA mixture of different grades of hydrophilic polymers, wherein the hydrophilic polymers comprise from about 0.1% to about 20% by weight of medium viscosity hydroxypropyl methylcellulose and from about 0.1% to about 20% of low viscosity hydroxypropyl cellulose.

Although the aforementioned formulations are generally described as sustained release formulations, such sustained release occurs only when the salt concentration, ionic strength, is low in the dissolution medium. The release rate of the active substance of the aforementioned formulations is substantially dependent on the ionic strength. High ionic strength may even lead to a so-called dose dumping effect. In this case, the total amount of active substance is released in a very short time, which may lead to an undesirably and even dangerously high blood level of active substance. High ionic strength often occurs directly after a meal. Since patients often take their medicine after meals, formulations affected by ionic strength have a high risk of undesirably releasing the active substance rapidly rather than the desired sustained release.

WO 98/47491 describes a sustained release formulation in which the control of the release of the active substance is based on the combination of two so-called [ intelligent ] polymers with opposite wetting properties, one polymer showing a tendency towards strong hydrophobicity and the other polymer showing a tendency towards strong hydrophilicity. This formulation prevents dose dumping effects only by enteric coating.

It is an object of the present invention to provide a sustained release formulation which is substantially independent of the ionic concentration of the dissolution medium, which is typically the gastrointestinal tract digestive juices, even when the formulation is uncoated. It is obvious to the person skilled in the art that the formulation should also meet the normal physical and medical requirements in the art, such as good flowability of the powder when tabletted, a crushing strength of at least 30 newtons (N) for compressed tablets, a friability of less than 1% at a compression force of between 10 and 40 kilonewtons, content uniformity and sufficient stability. It is further desirable that the formulations can be prepared using common formulation procedures and equipment, thus eliminating the need for significant capital costs.

This object is achieved according to the invention by a pharmaceutical hydrophilic gel forming matrix formulation which releases one or more active substances over a long period of time when exposed to the digestive juices of the gastrointestinal tract, characterized in that the release is substantially unaffected by ionic strength.

Prolonged release is defined as the (gradual) release of the active substance from the dosage form over a period of 45 minutes or more. This period of time typically begins with the administration of the dosage form, or begins with the start of an in vitro dissolution test (the instant the dosage form is contacted with the dissolution medium).

The term substantially unaffected by ionic strength means that the release rate profile of the active substance does not change significantly when the ionic strength (I) is varied between 0.05 and 0.45 mole/liter (according to general section 711: physical test and determination (+ -label content) in USP 24). The ionic strength (I) is defined as I-1/2 sigma cz_i ²Wherein c is the concentration of different ions in the solution, Z_iThe number of their respective charges (chemical and physical surgery 71 edition (Handbook of Chemistry and Physics 71)^stedition), David r.lide editions, pages 2-18, boston, CRC publishing company, 1990-.

While a coating is not necessary to achieve immunity to ionic strength, the formulation may be coated with a coating material as needed to achieve another desired effect, such as taste masking or coloration. Suitable coating materials are known in the art, for example HPMC, acrylic resins, ethylcellulose (compiled by Graham Cole, Pharmaceutical coating technology, Taylor & Francis Ltd.1995).

The hydrophilic gel forming matrix has a tablet dosage form or a multiparticulate dosage form, preferably containing a mixture of at least two hydrophilic high viscosity cellulose ethers. While the presence of hydrophobic cellulose ethers, such as ethyl cellulose, generally does not adversely affect the release properties of the present formulations, it is preferred that substantial amounts of such hydrophobic cellulose ethers are not present. A substantial amount of hydrophobic cellulose ether means that the amount exceeds 20% by weight of the total gel forming polymer.

Cellulose ethers are well known in the art and available in pharmaceutical grades and differ in the viscosity of solutions of cellulose ethers of different average molecular weights. Hydrophilic polymers for the purposes of this patent application are characterized by a viscosity that is divided into a low viscosity (less than about 1000 millipascals (mPas)), a medium viscosity (about 1000 to about 10,000mPas), and a high viscosity (greater than about 10,000mPas) in a 2% w/w aqueous solution.

Hydrophilic hydroxypropyl methylcellulose polymers (HPMC's) useful in the present invention may be available in different viscosity grades under the trade name HPMC' sAvailable from Dow Chemical Co., Ltd, and under the trade name Dow Chemical Co., LtdObtained from Shin Etsu chemical company.

Low viscosity polymers are, for example, MethocelMethocelMethocelMethocelAnd MethocelTheir 2% aqueous solutions have viscosities of 5, 15, 50, 100 and 50mPas, respectively, at 25 ℃.

Medium viscosity HPMC's are for example MethocelAnd Methocel K4M, which has a viscosity of 4000mPas in 2% aqueous solution at 25 ℃.

High viscosity HPMC's are for example MethocelAnd MethocelThe viscosities of their 2% aqueous solutions at 25 ℃ are 15,000 and 100,000mPas, respectively.

Hydrophilic hydroxyethylcellulose polymers (HEC's) useful in the present invention may be given different viscosity grades under the trade name HECAvailable from AQUALON corporation, and under the trade nameFrom Amerchol.

The low viscosity polymer is for example NatrosolAnd NatrosolThe viscosity of a 2% aqueous solution thereof at 25 ℃ was 10mPas and 20mPas, respectively.

The medium viscosity polymer is, for example, NatrosolAnd NatrosolThe viscosity of a 2% aqueous solution thereof at 25 ℃ was 200mPas and 1500mPas, respectively.

The high viscosity polymer is, for example, NatrosolAnd NatrosolThe viscosity of a 2% aqueous solution thereof at 25 ℃ was 4000mPas and 90000mPas, respectively.

In a preferred embodiment of the invention, the formulation comprises a mixture of high or medium viscosity hydroxypropyl methylcellulose (HPMC) and high or medium viscosity Hydroxyethylcellulose (HEC). The ratio of high or medium viscosity HPMC to high or medium viscosity HEC is from 1/0.85 to 1/1.2, preferably from 1/0.9 to 1/1.1, more preferably from 1/0.95 to 1/1.05 and most preferably 1/1. The formulation may optionally comprise a low viscosity HPMC. In this case, the ratio of high or medium viscosity HPMC to low viscosity HPMC is from 1/0.01 to 1/0.2 and preferably from 1/0.01 to 1/0.1, and more preferably from 1/0.02 to 1/0.05.

It has been unexpectedly found that formulations having the aforementioned composition can be used to prepare tablets having a release rate that is independent of the ionic strength of the normal range of gastrointestinal digestive juices. The normal range is 0.17 to 0.35 moles/liter.

In addition to being unaffected by ionic strength, the release control principle of the formulation is also substantially unaffected by pH in the range of pH 1.3 to pH 7.4. This means that the release rate of the active substance is not influenced by the pH, in which case the release of the active substance is not limited by the solubility of the active substance, in other words the difference in the release values (expressed in%) for a given point in time is less than 20% of the labelling request over the entire pH range from 1.3 to 7.4 (see Dissolution specification section (pages 1080-81), guide for Dissolution Testing of FIP solid oral Products (final manuscript, 1995), Journal of pharmaceutical information 1996 (drug information Journal 1996), paragraph 30, page 1071-84).

Due to their optimal properties as sustained release formulations, the formulations according to the invention are useful in the treatment of a range of diseases where sustained release properties are required. The active substances that can be formulated in sustained release formulations are active substances for the treatment of the following conditions: central nervous system disorders, including schizophrenia, paroxysmal anxiety (EPA) disorders such as Obsessive Compulsive Disorder (OCD), post-traumatic stress disorder (PTSD), phobias and panic disorders, major depression, bipolar disorders, parkinson's disease, generalized anxiety disorder, autism, delirium, multiple sclerosis, alzheimer's disease/dementia and other neurodegenerative disorders, severe mental retardation and movement disorders such as huntington's chorea or tourette's syndrome, anorexia, bulimia, stroke, addiction/dependency/craving, sleep disorders, epilepsy, migraine; attention deficit/hyperactivity disorder (ADHD); cardiovascular diseases include heart failure, angina pectoris, arrhythmia, myocardial infarction, cardiac hypertrophy, hypotension, hypertension such as essential hypertension, renal hypertension or pulmonary hypertension, thrombosis, arteriosclerosis, cerebral vasospasm, subarachnoid hemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, raynaud's disease, renal diseases such as kidney failure; dyslipidemia; obesity; vomiting; gastrointestinal disorders include Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), gastroesophageal reflux disease (GERD), motility disorders and conditions of delayed gastric emptying such as post-operative or diabetic gastroparesis, and diabetes, ulcers such as gastric ulcer; diarrhea; other diseases include gynecological diseases; osteoporosis inflammation; infections such as bacterial, fungal, protozoal and viral infections, particularly infections caused by HIV-1 or HIV-2; pain; cancer; chemotherapy-induced damage; tumor invasion; immune disorders; urinary retention; asthma; allergies; arthritis; benign prostatic hyperplasia; endotoxic shock; sepsis; diabetic complications.

Active substances of preferred formulations are active substances which can be used for the treatment of disorders of the central nervous system such as fluvoxamine (5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentanone O- (2-aminoethyl) oxime) or fluoroxinoxan ((+) -benzamide, N- [2- [4- [ (2R) -2, 3-dihydro-2- (hydroxymethyl) -1, 4-benzodioxine-5-yl ] -1-piperazinyl ] ethyl ] -4-fluoro); active substances for the treatment of cardiovascular disorders such as tedisamil (tedisamil) (N, N' -dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3.3.1] -nonane) or propranolol (propanol); or active substances for the treatment of gynaecological disorders, such as hormone replacement therapy, for example dydrogesterone, estradiol (estradiol) or conjugated estrogens the invention is particularly useful for the preparation of the active substance fluoroxingchun, preferably its monohydrochloride ((+) -benzamide, N- [2- [4- [ (2R)2, 3-dihydro-2- (hydroxymethyl) -1, 4-benzodioxine-5-yl ] -1-piperazinyl ] ethyl ] 4-fluoro-monohydrochloride) described in EP0138280 and EP307061, and for tedisamil, preferably its sesquifumarate (N, N' -dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3.3.1] nonane 1.5-hydrocarbenedioate), this compound is described in EP 0550383.

The invention also relates to a method for producing the aforementioned preparation, characterized in that,

(1) a core compressed from a mixture comprising one or more active substances and a mixture of at least two hydrophilic high or medium viscosity cellulose ethers, which is substantially unaffected by ionic strength, substantially prolongs the zero order release of the active substances; and

(2) the core is optionally coated.

The ingredients HPMC, HEC, active, pigment blend and slip agent (glide) are mixed in a suitable mixer. The powder mixture was mixed with sodium stearyl fumarate in a suitable mixer.

The active substance may be added to the powder mixture for compression in the form of a pre-granulated formulation. Further the powder mixture for tableting can be made via a mixing procedure followed by a (wet or dry) granulation process.

Component mixture using commercially available equipment (e.g.R0) compressed into tablets using flow control agents such asColloidal silica and lubricants such as talc, sodium stearyl fumarate or magnesium stearate. The hydrophilic cellulose content of the overall formulation is 15% to 99.5%, while the active substance content is in the range of 0.1% to 80%. The flow modifier or lubricant level is fixed to improve powder flow and prevent powder sticking to the dye walls or the punch head. The slip agent is present in an amount of 0.05% to 5% and preferably about 0.2%. The lubricant is present in an amount of about 0.05% to 5% and preferably about 0.4%. Due to commercial considerations, the powder mixture may be colored with 0.1% to 10% pigment blend. Typical pigment blends are commercially available, for exampleIn (1)

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The following examples are merely illustrative of further details of the invention and are in no way intended to limit the scope of the invention.

EXAMPLE 1 preparation of formulations not affected by Ionic Strength

Example 1a general preparation procedure

The silica colloid is first passed through a sieve. The screen preferably has a mesh size of 0.40 mm to 0.595 mm. The active substance is mixed with the hydrophilic cellulose, the colloidal silica, the pigment blend and, if desired, mannitol in a suitable mixer. The mixer is preferably a high shear mixer with the granulator in the off position. Sodium stearyl fumarate was sieved. The screen preferably has a mesh opening of o.40 mm to 5.95 mm. The powder mixture is compressed into tablets of predetermined dimensions. The compression apparatus is preferably a rotary machine such as Korsch and Courtoy apparatus. If desired, the tablets may be coated with water-soluble cellulose or cellulose derivatives, for example ethylcellulose or aqueous suspensions based on acrylic esters or organic solvents. The coating process is preferably carried out with a perforated tumbler (perforated drum) apparatus or an apparatus based on fluidized bed technology.

TABLE 1 uncoated tablet (core tablet) composition in mg/tablet

Material	Flucinkson marker content: 2 mg/tablet	Acetyl minophen (Acetaminophen) label content: 2.2 mg/tablet	Fluvoxamine maleate content marked: 100 mg/tablet	Labeling content of tedisamil dihydrochloride: 100 mg/tablet	Tedisamil sesquifumarate label content: 150 mg/tablet
						Fluocixan hydrochloride	2.18	n.a.	n.a.	n.a.	n.a.
Acetyl minophen	n.a.	2.19	n.a.	n.a.	n.a.
						Fluvoxamine maleate	n.a.	n.a.	100.00	n.a.	n.a.
Tidesazamide dihydrochloride	n.a.	n.a.	n.a.	124.4	n.a.
						Tedisamil sesquifumarate	n.a.	n.a.	n.a.	n.a.	240.0
HPMC K4M	69.63	69.63	17.00	125.2	81.0
						HPMC E5	7.50	7.50	12.50	20.0	14.0
HEC HX250PH	69.63	69.63	17.00	125.2	81.0
						Mannitol SD200	n.a.	n.a.	100.00	n.a.	n.a.
Silica gel body	0.30	0.30	0.50	1.60	4.0
						Pigment blend PB23015	0.15	0.15	n.a.	0.40	n.a.
Stearyl fumarate sodium salt	0.60	0.60	3.00	3.20	5.0
						Total weight of the tablet (mg)	150.00	150.00	250.00	400.00	425.00

n.a.: not applicable to

TABLE 2 several composition Properties

Tablet Properties	Flucinkson marker content: 2 mg/tablet	Labeling content of acetyl minophen: 2.2 mg/tablet	Fluvoxamine maleate content marked: 100 mg/tablet	Labeling content of tedisamil dihydrochloride: 100 mg/tablet	Tedisamil sesquifumarate label content: 150 mg/tablet
						Tablet size (millimeter)	5.5X 11.0 mm special shape	7.0 mm circle	8.0 mm round	Oval 8.0X 15.0 mm	Oval 8.0X 15.0 mm
Tablet weight (mg)	150	150	275	400	425
						Crushing strength (N)	83	75	144	71	90
Friability (%)	Not determined	Not determined	Not determined	0.4	0.05
						Release side painting	TABLE 4	TABLE 4	TABLE 4	TABLE 4	TABLE 4

Example 1b Release Properties of several formulations

The release of active substance from hydrophilic matrix tablets was measured in USP apparatus II using 50rpm rotating paddles, the tablets being placed in USP dissolution buffer medium made from disodium hydrogen phosphate 2 hydrate (2aq.) and citric acid 1 hydrate (identified respectively as code F, G, and H) at 0.05 molar concentration (M), 0.17M and 0.34M pH6.8, respectively, or the tablets being placed in a half-change dissolution medium, prepared from 0.1M aqueous hydrogen chloride in the first part of the test (90 minutes), and subsequently adjusted to 0.2M pH6.8 using trisodium phosphate 12 hydrate in the second part of the test. To increase the ionic strength of the aqueous solution during the test, sodium chloride was added to the solution. The 1 liter second partial dissolution medium contained sodium chloride in amounts of 0 g (dissolution medium a), 10 g (dissolution medium B), 15 g (dissolution medium C), 30 g (dissolution media D1 and D2) and 50 g (dissolution media E1 and E2), respectively. Sodium chloride was added only to the second part of the experiment in dissolution media B, C, D1 and E1. In dissolution media D2 and E2, 75% sodium chloride was added to the first part of the experiment and 25% to the second part. The release of the active substance was measured over a 16 hour period, sampled at every one hour interval for the first two hours, and sampled at every two hour interval for the following test period. Samples were analyzed on-line using an HPLC system or an ultraviolet spectrometer. The release of the different active compounds from the formulations is shown in tables 4a-4 c.

From the release profiles listed in tables 4a-4c it was concluded that the active substance released from the formulation according to the invention is substantially independent of pH and ionic strength, with release values differing by less than 20%. It was further concluded that there was virtually no difference between the release profiles when the ionic strength was increased at low pH (pH1.2) and higher pH (pH 6.8).

TABLE 3 dissolution Medium overview

Table 4a release as a function of time of several uncoated tablet ingredients

Table 4b. release of several uncoated tablet ingredients as a function of time

Table 4c release of tedisamil sesquifumarate uncoated tablets in a single dissolution medium as a function of time

Claims (7)

1. A pharmaceutical hydrophilic gel forming matrix formulation comprising one or more active substances and having a prolonged release of said one or more active substances upon exposure to gastrointestinal digestive juices, characterized in that the hydrophilic gel forming matrix comprises high or medium viscosity hydroxypropylmethylcellulose HPMC and high or medium viscosity hydroxyethylcellulose HEC in a HPMC/HEC ratio of 1/0.85-1/1.2 and optionally a low viscosity HPMC in a high or medium viscosity HPMC/low viscosity HPMC ratio of 1/0.01-1/0.2, and the release is substantially unaffected by ionic strength.

2. The formulation of claim 1, wherein the formulation is coated.

3. The formulation according to claim 1 or 2, characterized in that the active substance is fluvoxamine or a pharmaceutically acceptable salt of fluvoxamine or fluoroxingcine or a pharmaceutically acceptable salt of fluoroxingcine.

4. A formulation according to claim 3, characterized in that the active substance is fluoroxingchun monohydrochloride (+) -benzamide, N- [2- [4- [ (2R) -2, 3-dihydro-2- (hydroxymethyl) -1, 4-benzodioxine-5-yl ] -1-piperazinyl ] ethyl ] 4-fluoro-monohydrochloride.

5. The formulation according to claim 1 or 2, characterized in that the active substance is tedisamil or a pharmaceutically acceptable salt of tedisamil or propranolol or a pharmaceutically acceptable salt of propranolol.

6. A formulation according to claim 5, characterized in that the active substance is tedisamil sesquifumarate N, N' -dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3.3.1] nonane 1.5 hydrocarb dioate.

7. A process for preparing a formulation as claimed in any of claims 1 to 6,

(1) a core compressed from a mixture comprising one or more active substances, high or medium viscosity hydroxypropylmethylcellulose HPMC and high or medium viscosity hydroxyethylcellulose HEC in a HPMC/HEC ratio of 1/0.85-1/1.2, and optionally a low viscosity HPMC in a high or medium viscosity HPMC/low viscosity HPMC ratio of 1/0.01-1/0.2, resulting in substantially no ionic strength and substantially prolonged zero order release of the one or more active substances; and

(2) the core is optionally coated.