Pharmaceutical compositions containing hollow fine tubular drug delivery systems

Pharmaceutical compositions containing hollow fine tubular drug delivery systems

Ε. I. DU PONT DE NEMDURS AND COMPANY

C. 69353

05/01/86

12:40

LEGAL-WOODWARD

ND. 004

Title BP-6267

PHARMACEUTICAL COMPOSITIONS CONTAINING

BMW.HNS TUPUIAR DRUG DELIVERY SYSTEMS gysJmmM 9f rhe jnvmkn

Yield of Invention:

Thle invention relates to pharmaceutical con־ positions and note particularly to controlled release pharmaceutical compositions containing hollow tube drug delivery systems.

Bug!;

Controlled delivery or sustained release formulations have gained wide popularity in the pharmaceutical industry. The popularity of these formulations has grown due to the usefulness in 15 extending the utility of particular drugs which require specific dosages and delivery of the dosage at a noh-toxicological rate.

In the pharmaceutical industry* sustained release has been used extensively for ,oral medications 20 over a number of years. Sustained release formulations include encapsulated pellets or beads« enveric coated formulations, use of slightly soluble salts, drug complexes« and porous tablets containing dispersed drugs.

Controlled drug delivery on the other hand is 25 aimed at achieving sustained release 01. a drug at a constant rate (zero order) for long periods of time. Zero order release can be provided at the present time only by mechanical pumps« such as automatic syringes and implantable pumps, osmotic pumps such as Aiza's 30 systems known as Alzet*, Progestasertm and Ocusert.« chemically controlled biodegradable mechanisms, and diffusional systems based on polymeric membranes and matrices such as the currently marketed transdermsl systems for the delivery of nitroglycerin for angina 35 pectoris and scopolamine for motion sickness.

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Solid fibers have been need in sutures encapsulated with antibiotics and in intrauterine devices to release hormones.

While rnueh work hao been done over SKtny years 5 relating to the auetalnert raleaoo and the controlled release of drugs, there still 18 a need for now systems that are capable of delivering a predetermined amount of a drug at a predetermined rate, over a selected time. The present invention provides such systems.

Summary of The Invention

According to the present Invention there 18 provided a pharmaceutical composition comprising a pharmaceutically suitable carrier and at least one drug delivery system consisting essentially of (1) a polymeric fine tube having a membrane outer sheath and a hollow core, and (2) at least one dreg compound contalned within the core, said system conteined in the composition in an amount sufficient to del.'ver a 20 therapeutic amount of the drug contained therein at a predetermined rate over a predetermined per J. id of time.

According to a preferred embodiment, a plurality of hollow, porous, segmented polyurethane/ 25 urea tubes up to 15 cm in length containing .st least one drug in the core are contained in a pharmaceutical composition in the form of a tablet, capsule. euupension, suppository, or suture.

Detailed Description of the invention

The preparation of hollow tubes from polymers can be achieved by various routes. These ere referred to as wet. dry or melt-forming processes. Wait-forming involves heating a polymer above its melting point and 35 extruding it through an orifice (usually referred to

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NO.005 as a die} which is designed to form a hollow tube. Once extended« the melt is cooled via a quench which allows the polymer to solidify into a fine tube, in the dry-forming process, a solution of the poCymer is 5 extruded through a desired orifice and is fed into a heated column which allows for evaporation of the solvent and subsequent formation of a tube. In a wet-membrane forming process, a solution of the polymer is extruded though an orifice and quenched in 10 e non-solvent for the polymer resulting in coagulation of the polymer to a tube. Of the above mentioned forming processes, wet-membrane forming allows one to easily produce hollow porous tubos. It will be appreciated that the particular forming process uned 15 will be dependent upon the polymer used and type of hollow tube desired.

To make a membrene outer sheath in a hollow tube, one first dissolves or disperses a polymer to form a liquid solution, λ porous membrane results 20 *hen the latter process is reversed under controlled condition. The polymer coagulates into a continuous matrix as it separates from the solvent which forms a aiepacalon of droplets. As tue pulymei Bollfliries ano the solvent is extracted, the becomes a network of open poret. This phase inversion or separation can be achieved by a number of techniques. In one, the temperature of the oolvmer en1_ vent dictates the point at which the phase inversion occurs. In another, the polymer solvent is physically 30 evrhanzjei with a 901 1ס«ןvent fee tLe pvl/iuci uaualuy phase inversion.

The size of the pores is affected by the solvent strength of a polymer. A rapid decrease in solvent strength often tends to entrap a dispersion of 35 small droplets within the continuous polymer phase. A

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001 * elow decrease in solvent strength allows for nucleation sites within the polymer matrix allowing for formation of larger pores. In this case, the reduc tion in solvent strength must be rapid enough to allow S for the structure of the membrane to set.

Another way to change porosity and volume of the poroue network in the polymer is to change the concentration of the polymer solution. Lower concentrations have a tendency to promote larger pores and 10 greater pore volume. However, there is a limit to bow high (usually no more than 45% w/w) the polymer concentration can be in a solvent, otherwise, the polymer will become the dispersed phase in a continuous solvent phase, thereby eliminating the porous network.

Another method to achieve porous tubular membranes is to cause a rapid phase inversion of the polymer solution by cooling.

Generally, ae !ho yolynor Bonbtano o£ the hollow tube is quenched, the surface of the polymer 20 tends to have a *dense״ skin due to a rapid reduction of solvent strength at the surface. The interior, on the other hand, muet have the solvent diffuse and migrate through the polymer matrix. This results in larger interior pores. In a thermally induced quench, 25 the relative cooling rates can determine the relative degree of porosity.

Conventional machinery used in the manufacture of tubes often has a tendency to orient the polymer by either the mechanical features of the 30 device or by the intrience of gravity. This often results in distortion of pore shape and orientation in tubular membrane production and also requires that the solution have inherent physical properties enabling it to be processed on the conventional equipment. Hot 35 and cold drawing can also be used to vary the outside

05/01/B6 12:46 LEGft_-UOOIM«D NO. 006 002 -----־----- diameter of the tube and its cor. volume. Pot exampl.« a large diameter tube can be extruded and then drawn down to a small diameter.

In order to minimise the effects of orients5 tion and maximize the benefits of uniform porosity and allow for production of membranes from fragile polymer systems, a preferred tube forming process called density gradient membrane formation is used. This process uses density gradients in the phase inversion bath. Careful selection of the coagulation solutions allows one to use gravity to gently draw and collect the thin tubular membrane in the phase inversion bath. The density gradient of the coagulation solution can be established by either multiple stacked layers of liquids with different densities, or by the use of a single coagulant subjected to a temperature gradient which in turn produces a density gradient. Proper selection of the coagulation solution is extremely important when processing delicate membranes.

Depending on the density of the tube vs. the quench bath, it can be spun either upwards or downwards. For drug encapsulation, selection of the quench media is dependent on the drug solubility and miscibility of the solvent for the polymer.

In order to encapsulate a drug compound in the core of the hollow tube, either a suspension, solution, or other extrudable form of the compound has to be prepared initially. This is achieved by selecting a solvent for the drug and dissolving it to a

4U daaired coneantration os by melting the drug material to be encapsulated. Alternatively, a suspension of fine particles of drug in an appropriate liquid medium is prepared which can either be heated to form a liquid suspension that can be solidified in the coze of the tube or can be made viscous enough for the drug

05/01/86 12:47 LEGAL-bJOODUARD NO. 006 003 -------'0/37 to remain in suspension. Often a dilute solution of tho polymer used to make the tubular membrane outer sheath serves as an adequate suspending medium for the drug. Once the appropriate drug solution or su8pen-

8ion is made. it is pumped into the annular die simultaneously with the solution of the polymer forming the outer «heath of the hollow tube. Thio 1« echomat1cally illustrated in Figure 1. The resulting hollow tube containing the drug is quenched in an appropriate 10 poor solvent for the polymer )nd the drug and is permlvueO iv eev In tbc ^ucnob to a th. XC noooooory . OtlQ tube can be removed from the initial quench and placed in another solvent which can expedite removal of the remaining solvent in the tube, without removing the is drug. For example, a volatile non-solvent for the drug and tube can be used to exchange with any residual solvent remaining in the tube and subsequently be removed by vacuum extraction.

After the drug encapsulated hollow tube is 20 formed, the continuous tube is cut into lengths suitable for formulation into a pharmaceutical composition for administration to mammals, particularly in the form of a tablet, capsule, suppository, suspension, or suture. The length of the hollow tube can be as long 2s as can conveniently be formulated into a dosage form commensurate with the delivery of a therapeutic amount of the encapsulated drug. Formulations can be prepared making use of carriers, vehicles, diluents: excipients, and procedure« well known to those skilled in the 30 pharmacy art.

For example, the hollow tubular delivery system can be one continuous length that can be balled up¹¹ into a dosage form. The continuous tube may be more suitable for the slow release of a drug 35 over a long period of time via an osmotic pump

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In porosity. They ace normally melt formed at temperatures above 200*C but they can also be dissolved in solvents at elevated temperatures and then quenched.

Because of the high temperatures necessary for the fabrication of polypropylene hollow tubes, care must be used in selecting drugs which are not heat sens!tive. Alternatively, the drug can be Injected into the core of the hollow tube after it is formed: however, such a procedure is not preferred.

Polyurethanes, such as segmented polyurethane/ ureas sold under the name Lycra., can be dissolved at ambient temperature in dimethylacetamide (DMAC) or other appropriate solvent and fabricated into porous, hollow tubes at ambient temperature. They can also be 15 blended easily with water-soluble materials such as polyvinylpyrrolidone (PVP). polyethylene glycol (PEG), and salts which enhance porosity and wettability of the resulting tubular membranes. These tubes have high elasticity, are biocompatible, and offer great flexibility in the design of hollow tubular membranes, especially by the preferred density gradient membrane formation technique. Copolymers of ethylene-vinyl acetate with at least 33% by weight of vinyl acetate can be dissolved at ambient temperature in tetrahydro־ furan (THP) and fabricated into porous hollow tubes. They are easily blended with water soluble materials such as PVP, PEG, and salts. These tubular membrane systems are somewhat elastic, are biocompatible, and are easily formed into hollow tubes. Hytrel., a polyester elastomer, can also be formed into porous tubular membranes and blended with water-soluble polymers.

Polyvinyl alcohols can be dissolved easily in hot water at 60*C and can be fabricated into porous 35 hollow tubes at ambient temperatures. Because of

05/01/66

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LEGAL-UCCDUARD

NO.007 their solubility in water, they can be used as slowly erodible matrixes tor delivery of active Ingredients.

Any therapeutically active drug compound can be used. In the examples which follow, the following 5 compounas were chosen as models because of their broad range of chemical and pharmacological characteristics:

• Phenylpropanolamine hydrochloride, a decongestant. pKa (base) 9.5 ־, is freely soluble in water (25’C).

¹⁰ . Theophylline, an antiasthma drug. pKa (base) .36 with a solubility In water of 1 gram in 120 mis (25*C).

• Chlorpheniramine maleate, an antihistamine, pKa (base) - 8.99. has a solu־ ¹⁵ bility of 1 gram in 3.4 ml water (25*C).

• Salicycllc acid, a topical antiseptic.

pKa >2.97, 18 slightly soluble in water.

• Indomethacin, an antiinflammatory drug, pKa (acid) 4.5 =־. has a low solubility in water.

• Nalbuphine hydrochloride, an analgesic, pKa (base) > 8.4. 18 soluble in water.

In the Examples which follow, hollow tubes 2s were prepared by one of two procedures which can be varied depending upon the end results desired. Drugs were incorporated in the cores of the tubes via solutions or suspensions of the drugs.

Procedure A ³⁰ This procedure uses the arrangement shown in

Figure 1. in this procedure, a solution of the polymer for the outer membrane sheath is pumped through the annular die simultaneously with a solution of the core material which results in a tubular membrane surrounding core solution. This is passed through an

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NO. 007 annular die (O.D. 2.10 nun) into a quench tube containing 1 liter of a coagulant for the polymer.

The solvent 18 continuously removed from the polymer/ drug encapsulated system and it is collected in a rotating piddle pot. The loaded tube remains in the piddle pot as the solvent 18 being removed and Is removed after solvent removal Is nearly complete for further treatment, e.g. removal of trace amounts of solvent. The tube Is formed at a rate of 0.1 to 2 cm?/min and the speed of the piddle pot is the same as the speed of the tube as it exits the quench tube. Temperature of spinning and coagulation are controlled by heating mantles surrounding the die and coagulation kettle.

¹⁵ Table I gives Examples of drug loaded tubes which were formed by the above method. All runs were conducted at room temperature.

Procedure B

This procedure Involves membrane formation by 20 utilization of density gradients. This procedure Is desirable for most applications where membrane fabrlcation and drug encapsulation are involved. Due to excessive *draw which 16 inherent in most extrusion techniques and also to the difficulty of fabricating slow forming membranes or tubes whose polymer structure has weak physical characteristics, this procedure allows for membrane formation of polymers having any or all of the characteristics mentioned. By correctly choosing coagulante with a density slightly different than that of the polymer/drug encapsulated tube, one can use gravity to gently draw and collect a forming tube within the phase inversion bath (coagulant). If the bath density is less than the tube, the tube will sink and collect at the bottom of the bath (Figure

2). If the bath density is greater, the spinning

05/81/86 12:54 LEGAL-MEDUftRD bC.887 884 ־

Jb/37 device 18 Inverted and the tube will float upward and collect at the top of the phase Inversion stage (Fiyune 3), This procedure can use several bath fluids of decreasing density stacked vertically in the 5 tube allowing for flexibility in design to give the ability to use a sequence of quench-coagulation treatBents in the sane phase inversion unit. For example, a layer of a heavy liquid can be placed adjacent to tho die for thermal insulation. A lighter heat conductive liquid on top of this layer becones the quenching agent.

The encapsulation of drugs is accomplished by dissolving or suspending the drug in a suitable liquid, or melting the drug, then taking this drug preparation IS and loading it into a stainless steel piston used for inserting the core material, a second piston for the outer sheath membrane contains the polymer solution. Temperature control* if necessary, of the pistons, die* and coagulant is accomplished by heating jackets.

Die size is chosen depending on the diameter of the tube desired* and on the lumen desired. The rate at which the polymer and drug 18 pumped is controlled by settings on the pumps. The gap between the die and the top of the coagulation bath, where appropriate, is 25 set according to the amount of draw down'¹ desired.

in Tables I and II are given the conditions and characteristics of the tubes prepared using this procedure. All parts and percentages are by weight.

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The following abbreviations are used in the tables:

Polyaers and solvents!

Ur126 . Segmented polyurethane/urea (50.000 molecular weight} PVP-15 - Polyvinylpyrrolidone (15,000 molecular weight; 40 - 40.000 molecular weight)

PEG Polyethylene glycol (400 molecular weight; 740 molecular weight: 1000 molecular weight; 1300 molecular weight: 3350 molecular weight) PG - Propylene glycol EVA . Copolymer of ethylene-vinyl acetate with 331 by weight vinylacetate (melt index 43. density 0.95 g/cc)

NMP = l-Hethyl-2-pyrrolidone DMAC יי Dimethylacetamide thf « Tetrahydrofuran

D0W0X = Dowex BO cross-linked sulfonated polystyrene ion exchange resin

Drugs

Sal. Acid ־ Salicyclic acid PPA Phenylpropanolamine hydrochloride CM s Chlorpheniramine Maleate Nalb-HCl 8 Nalbuphine hydrochloride Theo יי Theophylline Ind ־ indomethacin

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12:55 L£GWL“UOODWARD NO. 007 006 ——. ! ״ ....

TABLB I

Hollow Thin Tubular Membrane Preparation With Encapsulated Druaa

<td> 5</td><td> Ex. KL.</td><td colspan="2"> Polymer</td><td> Core % in Susp. nr Soln.</td><td> Air Cap il!l£h££l</td><td colspan="2"> Direction of Membrane ESLESatifin Quench</td>

<td></td><td> 1</td><td> 34% Url26</td><td> (DMAC)</td><td> 3% Theo in PG</td><td> 0</td><td> A</td><td> H₂0</td>

<td></td><td> 2</td><td> 36% Url26</td><td> (MAC)</td><td> 10% Sal. Acid in PG</td><td> 0</td><td> A</td><td> h₂0</td>

<td> 10</td><td colspan="7"></td>

<td></td><td> 3</td><td> 36% Url26</td><td> (DMAC)</td><td> 3% Theo in PG</td><td> 0</td><td> A</td><td> h₂0</td>

<td></td><td> 4</td><td> 36% Vrl26</td><td> (DMAC)</td><td> 30% Sal. Acid in PEG 740</td><td> 0</td><td> A</td><td> h₂0</td>

<td> 15</td><td> 5</td><td> 36% Url26</td><td> (DMAC)</td><td> 30% Sal. Acid in PEG 1000</td><td> 0</td><td> A</td><td> h₂0</td>

<td></td><td> 6</td><td> 36% Url26</td><td> (DMAC)</td><td> 30% Sal. Acid in PEG 1300</td><td> 0</td><td> A</td><td> h₂0</td>

<td></td><td> 7</td><td> 36% Url26</td><td> (DMAC)</td><td> 25% Ind. in PEG 3350</td><td> 1</td><td> B(down)</td><td> 60% Ethanol in h₂0</td>

<td> 20</td><td colspan="7"></td>

<td></td><td> 8</td><td> 36% Url26</td><td> (DMAC)</td><td> 50% Walb-HCl in 3.6% Ur (DMAC)</td><td> 1/4</td><td> B(down)</td><td> 60% Ethanol in H₂0</td>

<td> 25</td><td> 9</td><td> 36% Url26</td><td> (DMAC)</td><td> 50% Balb-HCl in 3.6% Ur (DMAC)</td><td> 1/4</td><td> B(down)</td><td> 60% Ethanol in H₂0</td>

<td></td><td> 10</td><td> 36% Url26 15% PVP4Q</td><td> with (DMAC)</td><td> 25% Balb-HCl in 1.8% Url26 in DMAC</td><td> 1/4</td><td> 8( down)</td><td> 60% Ethanol in H₂0</td>

<td> 30</td><td> 11</td><td colspan="2"> 36% (Url26 + 25% PVP-15)(DMAC)</td><td> 25% Malb-HCl in 1.8% Url26 in DMAC</td><td> 1/4</td><td> B(down)</td><td> 60% Ethanol in H₂O</td>

<td></td><td> 12</td><td> 36% Url26</td><td> (DMAC)</td><td> 25% Balb-HCl in 1.8% Url26 In DMAC</td><td> 1/4</td><td> B(dotm)</td><td> 60% Ethanol in H₂0</td>

<td> 35</td><td> 13</td><td colspan="2"> 15% Blvanol KV (H₂0)</td><td> 50% PPA in 2% Blvanol in h₂0</td><td> 0</td><td> B(down)</td><td> 60% Bthanol in M₂O</td>

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<td colspan="5"> 15</td>

<td rowspan="3"> 5</td><td colspan="4"></td>

<td rowspan="2"> Ex. S2L.</td><td colspan="3"> Hollow Thin Tubular Meznbrana Preparation With Encapsulated Pruaa</td>

<td> Polymer is&amp;us&amp;u</td><td> Core % Air in Suap. Cap PF gP^t (Inches)</td><td> Direction of Meabrane I8n88il2a fluansh</td>

<td> 10</td><td> 14</td><td> 20% EVA 150 (THF)</td><td> 25% Theo in 1/2 3.6% Ur 126 (DHAC)</td><td> B(down) 60% Bthanol in H₂O</td>

<td></td><td> 15</td><td> 341 (ΡΠ24 4 25% PVP-15)(DMAC)</td><td> 25% Theo in 0 3.4% VH24 (DHAC)</td><td> B(down) 40% Bthanol in H₂O</td>

<td> 15</td><td> 14</td><td> Polypropylene</td><td colspan="2"> 33% Theo Hot spun (encapsulated 325 mesh in 3.4% in previously prepared Url24 (DHAC) tube</td>

<td></td><td> 17</td><td> 54% Vrl24</td><td> 50% CM in 1 3.4% Url26 (IMAC)</td><td> B(down) 80% Acetone in H₂0</td>

<td> 20</td><td> 18</td><td> 34% (Url24: PVP-15, IjI)</td><td> 33% (PPA-Powex) 0 in 3.4% Url24 (DHAC)</td><td> B(up) Deionized Distilled Water</td>

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008 --16

1&amp; dissolution rates of drug-filled hollow tubes whose preparation is shown in Table I were carried out by one of two procedures, one is a standard procedure described in the U.S. Pharmacopeia 5 XXi, page 1243 (1985). This procedure uses a 1 liter glass vessel immersed in water /it 30״C or 37^eC and filled with a specified amount of drug encapsulated tubes and an appropriate dissolution medium (0,1 N HC1, pH 7.4 phosphate buffer, buffered saline or 10 water). This vessel is stirred at a constant rate (25. 50 or 100 rpm) for the duration of the dissolution procedure and its contents ore sampled period!cally to determine the amount of drug released.

The second procedure, sometimes referred to 15 as the rotating bottle method, u8'ts sealed, cyllndrieal glass tubes immersed in water at 3O*C or 37״c and filled with drug encapsulated tubes and an appropriate dissolution medium as described above. The glass tubes are tumbled at a specified rate (15 rpm) 20 throughout the test and the contents are sampled periodically to determine the amount of drug released. The length of the tests vary depending on the rate of release of the drug (2-100 hours). Time should be long enough to allow significant (~>50t) release of 25 drug.

The in vitro dissolution procedures of Table I hollow tubes are shown in Table II along with the characteristics of the tubes. The dissolution results are discussed after Table 11.

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<td colspan="2"></td><td colspan="6"> Drug-encapsulated Thin Tubular Kembranes And Dissolution Rates</td>

<td> 5</td><td> Ex. 12j.</td><td> Menbrane Sheath</td><td> Drug A Susp. Axent</td><td> Tube Die. Tube (OD Length m.)</td><td></td><td> Drug Loading Ult. % vLJalal</td><td> Dissol. Proc.</td>

<td></td><td> 1</td><td> Url26</td><td> 3X Theo, in PG</td><td> 1.5 ״1 (2.54 cm)</td><td> Closed ends 70% Lumen Dia</td><td> 2%</td><td> USP 30*C/ 50 rpm¹</td>

<td> 10</td><td> 2</td><td> Url26</td><td> 10% sal. acid in PG</td><td> 1 1.5 (2.54 cm)</td><td> Closed ends 70% Lumen Dia.</td><td> 6.9%</td><td> USP 30״C/ 50 rpm¹</td>

<td></td><td> 3</td><td> Url26</td><td> 31 Theo, in PG</td><td> 1” 1.5 (2.54 cm)</td><td> Closed ends 60% Lumen Dia.</td><td colspan="2"> 2% rot. bottle 37 “C7 25 rpm¹</td>

<td> 15</td><td> 4</td><td> Url26</td><td> 30X sal. acid in PKG 740</td><td> 1- 3.6 (2.54 cb)</td><td> Closed ends 67% Lumen Die.</td><td colspan="2"> 12% roi. bottle 30. C/ 15 rptt¹</td>

<td></td><td> 5</td><td> Url26</td><td> 30% sal. acid in PKG 1000</td><td> 1 3.0 (2.54 cfi)</td><td> Gloatd ends 33% Lumen Dia.</td><td colspan="2"> 22% rot. bottle 30*C/ 1.5 rpm¹</td>

<td> 20</td><td> 6</td><td> Url26</td><td> 30% eal. acid in PKG 1300</td><td> 1” 3.0 (2.54 CB)</td><td> Closed ends 33% Lumen Die.</td><td colspan="2"> 20.2% rot.bottle 30״C/ 15 rpm¹</td>

<td> 25</td><td> 7</td><td> Url26</td><td> 25% Ind. in PKG 3350</td><td> 1- 2.3 (2.54 CB)</td><td> Closed ends 33% Lumen Dia.</td><td> 17%</td><td> USP 37*C/ 25 rpm¹</td>

<td></td><td> 8</td><td> Url26</td><td> 50:3.6 Valb-HCl: Url26</td><td> 1- 1.8 (2.54 cb)</td><td> C. osed and op an 82% Lwten Dia.</td><td> 56X</td><td> USP 37״C/ 50 rpm²</td>

<td> 30</td><td> 9</td><td> Url26</td><td> 50:3.6 Valb-HCl: Url26</td><td> 1 ,1/2 ״1 (1.27, 2.54 cm)</td><td> Open -50% Lumen Dia.</td><td> 39.8%</td><td> VSP 37.C7 50 rpm^</td>

<td></td><td> 10</td><td> Url26 &amp; 15X PVP-40</td><td> 25:1.8 Halb-HCl: Url26</td><td> 1 1 (2.54 cm)</td><td> Open and closed 50% Lumen Die.</td><td> 40%</td><td> USP 3/’C/ 50 rpm²</td>

<td> 35</td><td> 11</td><td> Url26 &amp; 25X PVP-15</td><td> 25:1.8 Valb-HCl: Vrl26</td><td> 1 1 (2.54 cm)</td><td> Open and dosed 67% Lunen Dia.</td><td> 56%</td><td> USP 37״C/ 50 rpm²</td>

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<td colspan="8"> 18 TABLE II (continued) Drug-encapsulated Thin Tubular M«tt&gt;ranep_Aad Dissolution Hates</td>

<td> 5</td><td> Ex.</td><td> Membrane</td><td> Drug &amp; Susp.</td><td> Tube Dia. Tube (OD</td><td></td><td> Drug Loading mt. %</td><td> .318801.</td>

<td></td><td> Wo j»</td><td> Sheath</td><td> Axent</td><td> Length mm.)</td><td> Cher.</td><td></td><td> J?£2L_</td>

<td></td><td> 12</td><td> Url26</td><td> 25:1.8 Valb-HCl: Url?6</td><td> 1 1 (2.54 cm)</td><td> Open and closed 74% Lumen Dia.</td><td> 66%</td><td> U8P 37.C/ 50 rp&gt;3^{1 2}</td>

<td> 10</td><td> 13</td><td> Blvanol HV •</td><td> 50:2 PPA: Blvanol HV</td><td> 1 0.8 (2.54 cm)</td><td> Closed ends 40% Lumen</td><td> 28%</td><td> USP 37*C/ 100 rpm²</td>

<td></td><td> 14</td><td colspan="2"> EVA 150 25:3.6 Theo:Ur!26</td><td> 1“ 0.8 (2.54 cm)</td><td> Closed ends 35% Lumen</td><td> 30%</td><td> USP 37״c/ 100 rpm²</td>

<td> 15</td><td> 15</td><td> Url26 &amp; 25% PVP-15</td><td> 25:3.6 Theo; Url26</td><td> 1“ 1.2 (2.54 cm)</td><td> Closed ends 40% Lumen</td><td> 51%</td><td> .’JSP 37’C/ 130 rpm²</td>

<td></td><td> 16</td><td> Polypropylone</td><td> 33:3.6 Theo: Url26</td><td> 1 1.2 (2.54 cm)</td><td> Closed ends 37% Lumen</td><td> 25%</td><td> USP 37״C/ 100 tpm²</td>

<td> 20</td><td> 17</td><td> Url26</td><td> 50:3.6 CH:Url26</td><td> 0.0 ,״1/8 ״1/2 (0.32 cm, 1.27 em)</td><td> open ends 75% Lumen</td><td> 28%</td><td> USP 37*CZ 100 .rpm²</td>

<td> 25</td><td> 18</td><td> 1:1 Vrl26: PVP-15</td><td> 33:3.6 PPA-Dowex Url26 (0</td><td> 0.68 ,״1/8 ,״1/4 ״1/2 ,0.64 ,32.</td><td> Tpen Ends 86% Lumen</td><td> 57%</td><td> USP 37״c/ 100 rpm³</td>

1.27 cm)

0.05 M pH 7.4 phosphate buffer ² distilled water ³ 0.1 VHC1

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The drug release patterns obtained with the pharmaceutical compositions of this invention cin be further understood by reference to the following examples in which temperatures are in degrees cent!5 grade.

Example 1

The dissolution of theophylline from hollow porous polyurethane tubes containing 2% theophyllini by weight was determined in pH 7.4 phosphate buffer at

30*c using the USP dissolution procedure. The tubes were prepared by encapsulating a 3% suspension of theophylline in propylene glycol in polyurethane 126 tubes prepared to have a 1.5 mm outside diameter with a 70¾ lumen diameter. The drug encapsulated tubes 15 were cut in one inch lengths and both ends were closed. The dissolution bath was stirred at 50 rpm. During the first hour, about 25¾ of the theophylline was released, followed by a sustained release with about 80¾ of the total theophylline being released by 20 11 hours.

Example^

The dissolution of salicylic acid from hollow porous polyurethane tubes containing 6.9¾ salicylic acid by weight was determined in pH 7.4 phosphate buffer at 30*C using the USP dissolution procedure. The tubes were prepared by encapsulating a 10¾ suspeneion of salicylic acid in propylene glycol in polyurethane 126 tubular membranes prepared to have a 1.5 mm outside diameter with a 70¾ lumen diameter. The tubes were cut to me inch lengths and both ends were closed. The dissolution bath was stirred at 50 rpm. Rapid release of 60¾ of the salicylic acid was observed during the first hour, followed by complete release over 3 hours.

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Example 3 The dissolution of theophylline from hollow porous polyurethane tubes containing 2* theophylline by weight was determined in pH 7.4 phosphate buffet at 5 37״c using the rotating bottle sustained release apparatus equipped with 50 ml bottles. The tubes were prepared by encapsulating a :.% suspension of theophylline in propylene glycol in {Olyurethane 126 tubular membranes prepared to have a 1.5 mm outside diameter 10 with a 60¾ lumen diameter. The tubes were cut in one inch lengths and both ends were closed. The bottles wore tumbled in the constant temperature bath at 10 rpm. During the first 1/2 hour, about 40% of the theophylline was released, followed by more constant 15 release to give complete dissolution over 4 hours.

Example 4 The dissolution of salicylic acid from hollow porous polyurethane tubes containing 12% salicylic acid by weight was determined in pH 7.4 phosphate 20 buffer at 30*C using the rotating bottle sustained release apparatus equipped with *סי ml bottles. The drug encapsulated tubes were prepared by encapsulating a 30% suspension of salicylic acid in polyethylene glycol 740 in polyurethane 126 tubes prepared to have 25 a 3.6 mm outside diameter with a 67% lumen diameter. The tubes were cut in one inch lengths with both ends closed. The bottles were tumbled in the constant temperature bath at 15 rpm. During the *irst 1/2 hour, about 30% of the salicylic acid was released.

followed by more constant release of 95% of the total salicylic acid over 6 hours.

Example 5

The dissolution of salicylic acid from hollow porous polyurethane tubes containing 22% salicylic 35 acid by weight was determined in pH 7.4 phosphate

05/01/86 13s02 LEQAL-WODUARD ISO. 007 013 — buffer at 30״C using the rotating bottle sustained release apparatus equipped with 50 ml bottles. The tubes were prepared by encapsulating a 30% suspension of salicylic acid in polyethylene glycol 1000 in poly5 urethane 126 membranes prepared to have a 3.0 mm outside diameter and a 33% lumen diameter. The tubes were cut in one inch lengths with both ends closed. The bottles were tumbled in the constant temperature bath at 15 rpm. During the first 1/2 hour, about 35% 10 of the salicylic acid was released followed by more constant release of 95% of the total salicylic acid over 6 hours.

Example 6 The dissolution of salicylic acid from hollow 15 porous polyurethane tubes containing 20.2% salicylic acid by weight was determined in pH 7.4 phosphate buffer at 30״c using the rotating bottle sustained release apparatus equipped with 50 ml bottles. The tubes were prepared by encapsulating a 30% suspension 20 of salicylic acid in polyethylene glycol 1300 in polyurethane tubes prepared to have a 3.0 mm outside diameter and a 33% lumen diameter. The drug loaded tubes were cut in one inch lengths with both ends closed. The bottles were tumbled in the constant 25 temperature bath at 15 rpm. During the first 1/2 hour, about 40% of the salicylic acid was released followed by more constant release of 78% of the total salicylic acid over 6 hours.

Example 7 ³⁰ The dissolution of indomethacin from hollow porous polyurethane tubes containing 17% indomethacin by weight was determined in pH 7.4 phosphate buffer using the usp dissolution procedure at 37⁰c. The tubes were prepared by encapsulating a 25% suspension 35 of indomethacin in polyethylene glycol 3350 in poly21

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urethane 126 tubular membranes prepared to have a 2.3 mm outside diameter with a 33% lumen diameter. The drug loaded tubes were cut in one inch lengths with both ends closed. The dissolution bath was stirred at 25 rpm. During the first 1/2 hour, about 42% of the indomethacin was released, fc!lowed by more constant release of about 85% of the total Indomethacin over 11 hours.

Example 8

The dissolution of nnlbuphlne hydrochloride from hollow porous polyurethane tubes containing 56% nalbuphine hydrochloride by weight was determined in distilled water using the USP t’lssolution procedure at 37’C, The tubes were prepared 5y encapsulating a mixture of 50 parts nalbuphine hydrochloride to 3.6 parts polyurethane 126 in polyurethane .126 tubular membranes prepared co have a 1.8 mm outside diameter with a $2% lumen diameter. The drug encapsulated tubes were cut in one inch lengths with either both tads closed or both ends left open. The dissolution b?th was stirred at 50 rpm. The open-ended tubes showed almost constant release of nalbuphine hydrochloride with complete release over 100 hours. The closed-ended tu?»es showed almost constant release of nalbuphine hydrochloride: however, only about 25% of the total nalbuphine hydrochloride had been released after 100 hours.

Example 9

The dissolution of nalbuphine hydrochloride from hollow porous polyurethane tubes containing 39.8% nalbuphine hydrochloride by weight was determined in distilled water using the USP dissolution procedure at 37^eC. The tubes were prepared by encapsulating a mixture of 50 parts nalbuphine hydrochloride to 3.6 parts polyurethane 126 in polyurethane 126 tubes prepared to have a 1 mm outside diameter and a 50% lumen diameter.

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The tubes were cut in one inch and in 1/2 inch lengths, giving tubular membranes having aspect ratios (length/ diameter) of about 25 and 12.5 respectively. The ends of the drug encapsulated tubes were left open. The dissolution bath was stirred at 50 rpm. Both sets of tubes showed virtually constant release of nalbuphine hydrochloride with the tubes with an aspect ratio of 25 resulting in release c׳f about 20% of the total nalbuphine hydrochloride over a 24 hour period while 10 the tubes with an aspect ratio of 12.5 resulted in about 65% of the total nalbuphine hydrochloride being released over a 24 hour p«ttiod.

Bxitmple 10

The dissolution uf nalbuphine hydrochloride 15 from hollow porous polyurethane tubes containing 15% polyvinylpyrrolidone and 40% nalbuphine hydrochloride by weight was determined in distilled water using the UB? diesolution procedure at 37*C. The tubes were prepared by encapsulating a mixture of 25 parts naibu20 phine hydrochloride and 1.8 parts polyurethane 126 in a tube containing 15% polyvinylpyrrolidone 40 in polyurethane 126 prepared to have a 1 mm outside diameter and a 50% lumen diameter. The drug encapsulated tubes were cut to one inch lengths and the ends were either closed or left open. The dissolution bath was stirred at 50 rpm. The open-ended tubes showed an initial release of about 5% of the nalbuphine hydrochloride during the first 1/2 hour, followed by a sustained release of 40% of the total nalbuphine hydrochloride by 24 hours. The closed-ended tubes showed a rapid release of about 4.5% of the nalbuphine hydrochloride during the first 2 hours, followed by a more sustained release of 8% of the total nalbuphine hydrochloride by 24 hours.

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The dissolution of nalbuphine hydrochloride fton hollow porous polyurethane tubes containing 25% polyvinylpyrrolidone 15 and 56% nalbuphine hydrochlor5 ide by weight was determined in distilled water using the USP dissolution procedure at 37*c. The tubes were prepared by encapsulating a mixture of 25 parts nalbuphlne hydrochloride to 1.8 parts polyurethane 126 in a tube containing 25% polyvinylpyrrolidone 15 in poly10 urethane 126 prepared to have a 1 mm outside diameter and g 67% lumen diameter. The drug encapsulated tube was cut to one inch lengths and the ends were either closed or left open. The dissolution bath was stirred at 50 rpm. The open-ended tubes showed a fairly con15 stant release with about 36% of the total nalbuphine hydrochloride being released in 24 hours. The tubes with the closed ends showed an initial release of about 5% of the nalbuphine hydrochloride during the first 1/2 hour, followed by sustained release to reach 20 10% of the total nalbuphine hydrochloride at 24 hours.

Example 12

In contrast to the dissolution observed in Example Ila the dissolution of nalbuphine hydrochloride from hollow porous tubes of polyurethane alone. 25 rather than the blended polymers used in Example 11. was found to be much slower. Tubes were prepared which contained 66% nalbuphine hydrochloride by weight by encapsulating a mixture of 25 parts nalbuphine hydrochloride and 1.8 parts polyurethane 126 in poly30 urethane 126 tubes with a 1 mm outside diameter and a 74% lumen diameter. The drug encapsulated tubes were cut to one inch lengths and the ends were either closed or left open. The dissolution was determined under the same conditions as those used for Example 35 11. The open-ended tubes resulted in only 4% disso24

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NO. 007 lution of the total nalbuphine hydrochloride at 24 hours, while the closed-ended tubes released only 1.5% of the total nalbuphine hydrochloride at 24 hours.

example !3 ⁵ The dissolution of phenylpropanolamine hydrochloride from hollow porous Elvanol HV tubes containing 28% phenylpropanolamine hydrochloride by weight was determined in distilled water using the USP dissolution procedure at 37*c. The tubes were prepared by 10 encapsulating a mixture of 50 parts phenylpropanolamine hydrochloride and 2 parts Elvanol HV in an Elvanol Hv tube prepared to have an outside diameter of 0.8 mm with a 40% lumen diameter. The drug encapeulated tubes were cut to one inch lengths and the ends were closed. The dissolution bath was stirred at 100 rpm. Complete release of the phenylpropanolamine hydrochloride was observed in the first two hours.

Example 14 The dissolution of theophylline from hollow 20 ethylene vinyl acetate tubes containing 30% theophylline was determined in distilled water using the USP dissolution procedure at 37*c. The tubes were prepared by encapsulating a mixture containing 25 parts theophylline to 3.6 parts polyurethane 126 in a 9E tubulac membrane of ethylene-viuy1 acetate copolymer (33% vinyl acetate by weight) prepared to have an outside diameter of 0.8 mm and a 35% lumen diameter. The drug encapsulated tubes were cut to one inch lengths and the ends were closed. The dissolution 30 bath was stirred at 100 rpm. After an initial release of about 20% of the theophylline during the first 1/2 hour, a constant release was observed resulting in complete release of the total theophylline by 24 hours.

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2«

The dissolution of theophylline from hollow porous polymethane tubes containing 25* polyvlnylpyrroildone and 51* theophylline by weight was determined 5 In distilled water using the US? dissolution procedure at 37״c. The tubes were prepared by encapsulating a mixture of 25 parts theophylline to 3.6 parts polyurethane 126 in a tubular membrane of polyurethane 126 polyvinylpyrrolidone 15 blend (25* polyvinylpyrroli10 done) prepared to have an outside diameter of 1.2 mm with a 40* lumen diameter. Ths drug encapsulated tubes were cut to one inch lengths and the ends were closed. The dissolution bath was stirred at 100 rpm. After an initial release of 20* of the theophylline in 15 the first 15 minutes a constant release was observed with complete release of the theophylline by 24 hours.

Example 16

The dissolution of theophylline from hollow polypropylene tubes with a mean wall porosity of &lt;0.1 20 um containing 25* theophylline by weight was determined In water using the USP dissolution procedure at 37״c. The tubes were prepared by encapsulating a mixture containing 33 parts theophylline to 3.6 parts polyurethane 126 in polypropylene tubes prepared to 25 have an outside diameter of 1.2 mm and a 3’.’* lumen diameter. The drug encapsulated tubes were cut to one inch lengths and the ends were closed. The dissolution bath was stirred at 100 rpm. After an initial *«lease of 11* of the theophylline in the first 1-2 hour.

sustained release wae observed with 80* of the tot«'l theophylline being released by 24 hours.

Example 17

The release of chlorpheniramine maleate from hollow porous polyurethane tubes containing 2U* 35 chlorpheniramine maleate by weight wau determined in

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J/ /37 distilled water using the USP dissolution procedure at 37*C. The tubes were prepared by encapsulating a mixture containing 50 parts chlorpheniramine maleote to 3.6 parts polyurethane 126 In a polyurethane 126 tubular membrane prepared to have an outside diameter of 0.9 mm and a 75% lumen diameter. The drug encapsulated tubes were cut to lengths of 1/8 inch (0.32 cm) or 1/2 inch (1.27 cm), giving tubes with an aspect ratio of 1.4 or 5.6 respectively and the er\ds were left open. The dissolution bath was stirred ar 100 rpm. The tubes with an aspect ratio of 1.4 should an initial release of 22% &lt;זי the chlorpheniramine maleate in the first 1/2 hour, followed by a sustained release to provide 85% of the total chlorpheniramine maleate at 8 hours. The tubes with an aspect ratio of 5.6 showed a constant release to provide 23% of the total chlorpheniramine maleate at V hours.

Release of phenylpropanolamine hydrochloride 20 (PPA) from open-ended hollow tubes whose eheat is constructed of a 1:1 blend of urethane Λ26 and polyvinylpyrrolidone and with aspect ratios of from 4.6, 9.2, and 18.6 were performed in 0.1 N HC1 nmc.\compared to that obtained with the core material. T4S' release 25 pattern for the drug encapsulated tubes was sustained after an Initial burst of 2. 3, and 6% (in 1/2 hour) and at 24 hours was about 42%, 60% and 70% for the small, medium, and low aspect ratio tubes respectively. The core component showed a faster release of PPA with 30 a burst of 30% in &lt;1/2 hour up to 100% in 20 hours.