CA1217139A

CA1217139A - Matrix composition for transdermal therapeutic system

Info

Publication number: CA1217139A
Application number: CA000453442A
Authority: CA
Inventors: David J. Enscore; Robert M. Gale
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 1983-05-04
Filing date: 1984-05-03
Publication date: 1987-01-27
Also published as: BE899444A; AU2717184A; FR2545357B1; FR2545357A1; NL8401262A; SE463012B; IT8467445A1; SE8402389D0; ZA843037B; JPS59206307A; AU558304B2; NL190508C; KR890000650B1; US4559222A; SE8402389L; IT8467445A0; KR840009035A; IT1179635B; GB8407741D0; ES532228A0

Abstract

ABSTRACT OF THE DISCLOSURE
Mineral oil (MO) polyisobutylene (PIB), colloidal silicon dioxide (CSD) mixtures suitable for use as drug containing matrices in transdermal delivery systems are disclosed.
Preferred systems for dispensing moderately mineral oil soluble drugs contain at least about 6% CSD, have a MO/PIB of at least 1.0 and a viscosity of at least 1.5 x 108 poises. Preferred systems for dispensing clonidine have a clonidine permeability of at least 1.0 x 10-4 µg/cm sec and a MO/PIB of at least 1.2.

Description

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Field of the Invention This invention relates to devices for delivering drugs and other active agents to the body and more particularly to a matrix composition having the characteris~ics of permeability, viscosity and adhesion desired for transdermal drug delivery systems.

Background of the Invention Various types of systems are known to the art for delivering biologically active agents (hereinafter "drugs") to the skin. These devices range from simple drug loaded creams, oin~ments and gels which are applied directly to the skin such as a nitroglycerin ointment for the treatment of angina, to more precisely controllable systems in which a drug is dispersed through a matrix of fixed configuration such as is shown in United States Patent 3,923,939 to even more sophisticated systems which employ rate con-trolling membranes or other structures to precisely me*er the quantity of drug that is administered through the skin for a prolonged period of time such as disclosed in United States Patents 4,~31,894 and 4,201,211, for example.
Regardless of the actual structure of any particular system, all these systems utilize some form of a reservoir for the drug in which the drug to be dispensed is dispersed and this reservoir must ` ,.) 3~

have certain characteristics of viscosity, permeability, and adherence in order to render it suitable for use in a delivery system. This is particularly important in laminated systems without sealed edges such as described in the latter two patents, where the adhesive and reservoir layers must be viscous enough to prevent oozing of the layers. The latter two patents dis-close mineral oil-polyisobutylene (M0-PIB) matrices for use in dispensing clonidine and scopolamine and such matrices are also useful for dispensing to the skin any moderately mineral oil soluble drug. Particularly suitable are those drugs whose solubility in mineral oil does not exceed approximately 5 mg/ml such as, in addition to clonidine and scopolamine; estradiol, ~
phenylpropanolamine, propranolol, ouabain, salbutamoll guanabenz, labetolol, atropine, haloperidol, bromocryptine, chlorophenira-mine, metrifonate, isosorbide dinitrate, and nitroglycerin, for example.
In addition to the primary drug or drugs, the compositions may also contain other materials such as permeation enhancers to improve skin permeability, cytoprotective agents to reduce skin irritation, buf~ers to adjust pH and other materials all as is known to the art.
As disclosed in the latter two identified patents, a typical M0-PIB matrix composition will comprise a mineral oil of about 5 to 100 cp viscosity at 25 C admixed with a blend of PIBs. The M0 usually constitutes between 35%-65% by weight of the mixtllre and the PIB can also constitute between 35%-65~ of the mixture. The PIB blend usually comprises a 10W mclecular weight (LMW) PIB (35,000-50,000 viscosity average molecular - weight) and a high molecular weight (HMW) PIB, (1,000,000 to 1,500,000 viscosity average molecular weight). Preferred mixtures comprise 35%-65% mineral oil, 10-40% LMW PIB and 10-40p HMW PIB. The precise formulation of any reservoir composition ; is generally adjusted to try to provide a particular combination of characteristics such as viscosity, drug permeability and adhesion as required 'co meet the design requirements of the lS end product. In general, the PIB functions as a thickener and the M0 as the solvent for the drug. Thus increasing the M0/PIB
ratio generally increases permeability and decreases viscosity .
while decreasing the MO~PIB ratio has the opposite effects.
It should also be noted, as disclosed in the latter two patents, that the same general M0-PIB mixtures can be tailored to be used either as a drug reservoir or as a contact adhesive for attaching the device to the skin and the adhesive may or may not contain an amount o~ drug material to provide a priming dose.
Typically, the drug to be dispensed is dissolved and dis-persed throughout the matrix material in amounts higher than saturation such that the reservoir contains both a dissolved and dispersed phase. The dispersed phase is normally present in amounts sufficient to maintain the concentration of the drug in matrix at or above saturation during the intended dispensing li~e of the deviceO While amounts as high as 40%

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by weight of drug can be included, normally a matrix for use as a drug reservoir would contain up to about 20% by weight of drug and when used as the adhesive, with a priming dose, up to about 10% by weight of drug.
In attempting to optimize matrix compositions, we have determined that the compositions should have a viscosity of no less than about 1.5 x 107 poise and a sufficiently high permeability, DCs, ~or the drug to be delivered to permit adequate release rates with reasonable size skin patches. With ; lS this combination o~ characteristics the drug delivery systems would have excellent physical characteristics in that they would retain their structural integrity, not ooze or ~low, be readily removed from the package in which they are contained, be reasonably sized and9 for the laminated systems, have a su~ficiently high permeability to permit the rate controlling membranes to be the predominant means for controlling the rate of drug release from the system.
It was known~that the viscosity of the matrix composition - could be modified by varying the M9/PIB ratio. HowPver, increasing the ~iscosity by increasing the proportion of PIB
results in a decrease in the permeability of the system ko ; 30 undesirably low levels. Correspondingly, increasing the mlneral oil content to raise permeability, yields lo~ viscosity ;~ compositions which tended to cold flow and have poor structural characteristics. Prior to our in~ention, for example, an ~ ~ ~t~ ~

MO/PIB ratio of about 1.0 was the highest feasible level for use in commerc.ially marketable transdermal systems.
Colloidal silicon dioxide (CSD~ such as Cab-O-Sil~
manufactured by the Cabot Corporation and other similar colloidal silica materials are know thickeners for mineral oil (see for example, Cab-O-Sil~ Properties and Functions, Cabot Corporation, 125 High St., Boston, MA 02110). It was also known by others to use CSD to thicken other types of drug matrices. In addition, CSD
is approved by the FD~ as a material generally recognized as safe for inclusion in topical pharmaceutical preparations~
Accordingly, it was decided to use CSD to increase the viscosity of MO-PIB matrix compositions. When amounts of CSD
were added to certain MO-PIB compositions, it was unexpectedly found that the viscosity could be increased without decreasing the permeability and, in fact, within certain composition ranges of the various components of the matrix composition mixture, it was possi~
ble to produce MO-PIB compositions having not only increased vis-cosities but also increased drug permeabilities as well. Further within certain ranges, unexpected improvements in other properties of transdermal therapeutic systems using these compositions were obtained.

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Thus in the prior art systems the mechanical and diffusional properties of the system were not independently variable (i.e., an increase in permeability invariably led to a decrease in the system viscosity, and vice versa). According to our invention, however, the use of CSD in certain formulations permits these properties to be independently variable and high permeability and high viscosity are both obtainable.

Accordingly, this invention seeks to provide a matrix composition for a drug delivery system having improved properties.

Additionally this invention seeks to provide matrix compositions having both high viscosities and high drug permeabilities.

Further, this invention seeks to provide a drug loaded mineral oil-polyisobutylene composition having a viscosity of a~ least 1.5 x 107 poise.

In another aspect, this invention seeks to provide a drug loaded matrix formed from mineral oil, PIB, CSD and a moderately mineral oil-soluble drug composition dispersed therethrough at a concentration above saturation.

This invention also seeks to provide a rate controlled transdermal therapeutic system having a mineral oil-polyisobutylene matrix with desired properties of viscosity, permeability and adhesion.

, These and other ~spects of the invention will be readily apparent from the following description of the invention witn reference to the accompanying drawings in which:

DESCRIPTION OF THE DRAWINGS
l0 Figure 1 is a schematic sectional view through a laminated transdermal therapeutic system;
Figure 2 is a graph showing the relationship between the CSD content of MO-PIB gels and the viscosity of clonidine and lS scopolamine compositions;
Figure 3 is a graph showing the relationship between MO/PIB
and in vitro clonidine release rates;
Figure 4 is a graph showing the effect of CSD content on release of packaged transdermal systems, and;
Figure 5 is a graph showing the relationship between MO/PIB
and permeability to clonidine and scopolamine.

~5 DESCRIPTlON OF THE INVENTION
According to this invention, we have discovered that it i5 possible to f~bricate MO~PIB matrix compositions having viscosities above 1.5 x 107 poise and high permeabilities for moderately mineral oil soluble drug compositions. As used herein, a ~oderately mineral oil soluble drug is a drug whose solubility in mineral oil is at least 10 ~g/ml and no greater than approximately 5 mg/ml. Non~limiting examples of such drugs are, scopolam~ne, clonidine, estradiol, phenylpropanola-,. . .. . . .

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, mine, propranolol, ouabain, salbutamol, guanabenz, labetolol~
atropine, haloperidol, bromocryptine, chloropheniramine, metrifonate, isosorbidedinitrate, and nitroglycerin, for example.
These viscosity and permeability characteristics can be obtained if the M0/PIB ratio is greater than about 1.0 and preferably in the range o~ 1.4-1.8 and the composition contains at least 5% and per~erably 7.5% to 10% colloidal silicon dioxide (CSD).
Such matrix compositions are capable of being loaded with up to about 40% by weight o~ moderately mineral oil-soluble drug compositions. In practice, however9 when used as a drug reser-voir, the loadings rarely exceed 20% and when used as an adhesive, rarely exceed 10%.
Referring now to Figure 1 9 a typical transdermal delivery system according to this invention would comprise a bandage 10 preferabl~ formed from an impermable backing 11, a reservoir layer 13 formed of a matrix material having drug 14 dispersed therethrough at a concentration greater than saturation, a drug relea~e rate controlling layer 15 such as a permeable or microporous membrane through which drug may di~use at a known rate, an adhesive layer 16 which mày also contain a loading o~

drug 17 and a protective strippable coating 18. The various layers are laminated or otherwise assembled into a bandage having a predetermined size and shape all as known to the art.
Figure 1 describes a preferred embodiment but it should be recognized that one or m~re o~ the layers may be deleted or 3S repeated, the basic tr~nsdermal system being a drug contair.ing ~7~

matrix provided with means for maintaining the matrix in drug transferring relationship with the skin.
In the following examples, adhesives and reservoirs having matrix compositions according to this invention are compared to the prior art control samples. In all the following examples, the M0 and PIB were initially mixed together under ambient conditions to form a gel. Thereafter the drug composition and CSD (Cab-0-Sil~ M-5 and M-7), if any, were added with mixing to provide a uni~orm dispersion. The sample transdermal thera-lS peutic systems 1.78 cm in diameter (area, 2.5 cm2) made from sùch compositions were fabricated having reservoir layers approximately 50 ~m thick, contact adhesive layers approximately 50 ~m thick and rate controlling membranes of 25 micron thick microporous polypropylene membrane (commercially available under the trademark Celgard~ 2400) saturated ~ith M0 (0.9 mg M0/cm2) all laminated together with an impermeable backing and a strippable liner as described in patents 4,031,894 and -: 25 4,201,211. In some cases where the adhesive composition adhered too ~trongly to the release liner~ a 5-10 micron thick prim~ -coat of 53~ PIB/47% M0 was applied between the adhesive and the liner. The M0 used was a light mineral oil having a o viscosity of 7 CP at 25 C, the LMW PIB had an average molecular weight of about 35,000 and the HMW PIB had an average molecular weight a~ about 1,200,000.
It should be noted that in the following examples, the compositions o~ the adhesive and .eser~oir matrices are the .

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compositions used in the fabrication of the delivery system.
Since the M0/PIB ratio for the adhesive and reservoir matrices i9 different and the Celgard~ layer is saturated with mineral oil; on standing the systems will equilibrate as a result of the transfer of mineral oil from the composition having a higher M0/PIB ratio to the lower. There will, however, be no significant transfer of drug since both the adhesive and reser-voir layers are above saturation and the excess undissolved drug in the matrices is not readily susceptible to mass transfer.
Therefore, on standing, the overall value o~ M0/PIB of the delivery system will be intermediate that of the initial M0/PIB
ratios, the exact value of which will depend upon the relative amounts o~ the materials used in each of the reservoir and adhesive layers, as well as the amount of mineral oil which is in the Celgard membrane, and, of course, the time and tempera-ture of storage.
In the following descriptions the compositions are defined in weight % of the matrix gels, disregarding structural elements of the TTS such as the backing members, release liners and rate control membranes.

Lxample 1.
A contact adhesive composition according to the prior art was fabricated from ~7~ M0, 27.8% LMW PIB, 22.2% HMW PIB
(M0/PIB = 0.94) and 3~ clonidine. A drug reservoir composition according to the prior art was fabricated containing 47g M0, ! ,! ' , '' . - ~, 22.2% LMW PIB, 17,8% HMW PIB (MO~PIB = 1.18) and approxima~el~
13~ clonidine. Clonidine transdermal systems were fabricated from these materials as described above and the systems exhibited an apparent viscosity at 40 C of approximately 8 x 106 poise.

Example 2.
Since the Clonidine TTS of Example 1 exhibited low viscosity, systems were prepared from a series o~ adhesive and reservoir compositions corresponding to the compositions of Example 1 but with 1%, 2%, 5% and 7.5% CSD added at the expense of all other ingredients. The effect of the addition of CSD on apparent viscosity of the TTS is shown in Figure 2.

Example 3 Contact adhesive and reservoir compositions containing scopolamine according to the prior art were fabricated from respectively, 46.1% M0, 28.9 % low molecular weight PIB, 23.0%
high molecular weight PIB and 2.0% scopolamine and 41.7% M0, 26.2% LMW PIB, 20.8% HMW PIB and 11.3% scopolamine. ~ series o~ adhesive and reservoir compositions correspon~ing to the above but having 1%, 2%, 5% and 7.5% CSD added at the expense o~ all other ingredients was also prepared. The effect of CSD
concentration on apparent viscosity of scopolamine transdermal system is also shown in Figure 2.

, - Example 4 Contact adhesive and reservoir compositions at varying M0/PIB ratios without CSD, with 7.5g CSD added at the expense of the PIB fraction of Example 1 and with 7.5~ CSD added at the expense of all other ingredients of Example 1 were made and formed into transdermal systems. By adding the CSD at the expense of the PIB it was possible to increase the value of MO/PIB as`can be seen from Table I, below. The effect of the variation in MO/PIB tincluding MO in the Celgard layer) on the clonidine release rates from the transdermal systems fabricated from these compositions is shown in Figure 3. As can be seen from Figure 3 the higher MO/PIB values obtainable by adding the CSD at the expense of the PIB fraction produce release rates significantly higher than had heretofore been obtained.
Table I summarizes other data obtained on systems manufactured according to Examples 1, 2 and 4.

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TTS(clonidine) System Comparison Example 1 Example 2 ExamDle 4 Attribute (No CSD) 7.5% CSD 7.5p CSD
(Expense of All) (Expense of PI~
Wt~ clonidine in 13.0 12.0 13.0 Drug Reservoir (D.R.) Wt~ clonidine in 3,0 2.8 3.O
Contact Adhesive (C.A.) ,, _ ~ . . . . .
Wt~ mineral oil in C.A. and D.R. 1~7.0 43.5 47.0 MO/PIB Ratio in D.R. 1.18 1.18 1.45 ~ .
MO/PIB Ratio in C.A. 0.94 0.94 1.11 MO/PIB Ratio Overall ~incl. MO in Celgard) 1.28 1.28 1.45 (excl. MO in Celgard) 1.06 1.06 1.28 Prime Coat Thickress (microns) 7.5 7.5 7,5 ., . . ....... . ... ~
DCs (~g/c~ sec) 2x10-5 2x10 5 1.2x10-4 ~, ~ ~ .. .. . .... _ _ _ . _ _ _ . .. , .. _ . _ _ .. _ _ _ _ _ nelease ~ate in vitro ~ 1.6 1.6 2.4 (~g/cm2.hr) _ ..... _ _ . _ . . . . . . , _ . ... . _ . .. _ . _ Apparent Gel Viscosity (Poise) 1.73 x 106 2.50 x 10~ 1-35 x 1~8 (0-24 hr creep) .. . . . . _ ..
System Backing/
Drug Reservoir 60 79 + 12 69 ~ 7 Adhesion (g/cm) 14_ As shown in Table I the products produced by Examples 2 and 4 both exhibited an improvement in viscosity o~ approximately two orders of magnitude from the product of Example 1. The product of Example 4, however, also exhibited an order of magnitude improvement in drug release rate from the product of Example 2 with no signi~icant decrease in viscosity resulting from the elimination of a portion of the PIB used as a thickener.

Example 5 Transdermal systems for dispensing clonidine and scopolamine were manufactured as described above from selected reservoir and adhesive composition described in Examples 1-4 and were subjected to package integrity testing. In this test the systems are packaged in sealed foil pouches and allowed to stand at ambient conditions for a minimum of 1 month until equilibrium conditions are approached. During this storage time the systems are vulnerable to cold flow of the adhesive and reservoir layers from their exposed edges which can impair removal from the pouch. Thereafter, the pouches are opened in the normally - -intended manner and the damage, if any, sustained by the TTS
upon opening is observedO The possible conditions observed after opening the pouch with the casualness of the ordinary consumer, turning it upside down and shaking are:

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,9 a) the TTS falls freely.from the pouch;
b) The TTS adheres to the pouch at its top side (side opposite the release liner) and peeling up on the release liner in an attempt to free the TTS from the pouch results in either:
1) the intact TTS separating from the pouch in usable form or

- 2) the release liner coming off with the top side still adhering to the pouch, an unusable condition;
c) the TTS adhering to the pouch at its release liner side and peeling up on the release liner allows removal of the intact TTS from the pouch or;
d) the release liner adheres to one side of the pouch and the top adheres to the other side of the pouch causing irrepairable damage to the TTS on opening OL the pouch.
Figure 4 shows the composite results of this test on a large number of clonidine and scopolamine systems.
As can be seen, the incidence of failure was significantly 25 reduced at CSD concentrations greater than 5~,.equivalent to a vi-sc-osity of at least 1~5 x 107 poise (see Figure 2).

Example 6 ~ A series of M0-PIB.compositions at varying M0/PIB ratios were prepared and the permeability of the compositions to clonidine and scopolamine were determined. The results are shown in Figure 5~ A3 c~n be seen significant improvements in permeab-lity are obtained at higher M0/PIB values. With respect ~16-to clonidine, values of 1~2 or above provide permeabilities greater than 1x10-4 ~g/cm sec which permits system to be designed in which the rate controlling membrane provides 'he predominant control meohanism of release rate.

Example 7 Propranolol base loaded M0-PIB matrices were prepared having varying CSD loadings and the effect of CSD on in vitro permeability determined. Table II shows the effect of addition o~ Cab-0-Sil in M0/PIB monolithic systems on the transport properties of propranolol base at various percentages.

Table II

SAMPLE SAMPLE SAMPLE
A B C

M0 % 36.l~ 35.2 34.0 LMW PIB % 41.1 39.8 38.5 Propranolol % 15 15 15 CSD % 7.5 10 12.5 M0/PIB 0.88 0.88 0.88 DCs 4.8 x 10 5 6.6 x 10-4 2.5 x 10-4 (~g/cm.sec) Discussion of Results As seen from Figure 2 the addition of CSD to M0-PIB systems increases the viscosity of the gels. At aboùt 3% CSD adequate viscosity is obtained even for such fluid systems as scopolamine and the viscosity tends to peak at about 5~ CSD. Further addition o~ CSD does not produce a proportional increase in , ; , .

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viscosity. Thus it would be expected that no significant improvement in physical properties of transdermal systems manufacture therefrom could be obtained at higher CSD levels.
Nevertheless the results of the package opening tests described in Figure 4 show a significant improvement in free falls above 5% CSD. By merely raising the CSD content from 5% to 7.5% the percent of free falls increased from 17.5% to 90% for the clonidine systems and from 10% to 79~ for the scopolamine systems.
Prior to this invention the maximum M0/PIB ratio obtainable in a M0-PIB composition having adequate viscosity for the purposes contemplated herein was approximately 1.00O As seen in Figure 5 at this ratio the permeability to certain drugs such as clonidine is lower than desired. Since the PIB is the thickening agent in M0-PIB gels, one would expect that as the M0/PIB ratio in any given system is increased, the viscosity would decrease. Also one would expect that as the viscosity of the M0/PIB gel increases as a result of the addition of CSD
the drug permeability in the gel at a constant MO~PIB ratio would decrease. However, as can be seen from Table I, adding the CSD at the expense of the PIB fraction produces no signifi-cant reduction in viscosity from that obtained by adding the CSD at the expense of all the ingredients. Also as shown by Table II the permeability of M0 PIB matrix actually increases, (at a constant M0/PIB ratioj with the addition of up to about 10~ CSD.

`~ ( ( -18_ According to this invention therefore we provide MO-PIB -CSD mixtures having no less than about 6% CSD (on a drug-free basis) and preferably from 6-11% which have an extremely good combination of properties for use as matrices for dispensing a wide variety of moderately mineral oil soluble drugs. Further when these compositions are fabricated with M0/PIB ratios greater than about 1.0 drug permeabilities heretofore unobtain-able are realized. In addition compositions according to this invention having MO/PIB ratios greater than about 1.2 can be used to to produce clonidine loaded matrices havin~ clonidine permeabilities heretofore unobtainable. When used in fabricating laminated TTS's in which the microporous rate controlling membrane is saturated with MO the overall MO/PIB of the system can actually exceed about 1.45 while retaining desirable structural characteristics.
Having thus generally described our invention it will be apparent that various modifications can be made by workers skilled in the art without departing from the scope of this invention which is limited only by the following claims --wherein: -

Claims

THE EMBODIMENTS OF TIE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition of matter suitable for use as a matrix in drug delivery system comprising mineral oil, polyisobutylene and at least 5%
colloidal silicon dioxide, the mineral oil/polyisobutylene ratio being at least 1.0, and being characterized by having a viscosity of at least 1.5 x 107 poise.

2. The composition of Claim 1 further comprising up to 40% of a moderately mineral oil soluble drug dispersed therethrough.

3. The composition of Claim 2 wherein said drug is present at a level between the saturation concentration of said drug in the composition and about 20%.

4. The composition of Claim 3 wherein the ratio of mineral oil to polyisobutylene is at least 1.2 and the composition contains at least 7.5%
by weight colloidal silicon dioxide.

5. The composition of Claim 4 wherein said drug is selected from the group consisting of clonidine, scopolamine, propranolol, estradiol, phenylpropanolamine, ouabain, salbutamol, guanabenz, labetolol, atropine, haloperidol, bromocryptine, chloropheniramine, metrifonate, isosorbide dinitrate and nitroglycerin.

6. The composition of Claim 1 wherein said drug is clonidine and the permeability of the composition to clonidine is at least 1.0 x 10-4 µg/cm sec.

7. The composition of Claim 6 wherein the value of mineral oil/poly-isobutylene is at least 1.2.

8. In a transdermal therapeutic system, comprising a drug reservoir layer and an adhesive layer, a moderately mineral oil soluble drug dispersed in at least said reservoir layer at a concentration above the saturation concentration of said drug in said layer and a drug release rate release controlling membrane disposed between said reservoir and adhesive, said reservoir and said adhesive layer comprising a mixture of mineral oil and polyisobutylene, the improvement wherein said reservoir and said adhesive layer contain at least about 5% colloidal silicon dioxide, have a viscosity of at least 1.5 x 107 poise and a ratio of mineral oil to polyisobutylene in the reservoir and ad-hesive of at least 1.2.

9. The transdermal therapeutic system of claim 8 wherein said release rate controlling membrane contains mineral oil and the overall ratio of mineral oil/polyisobutylene in the transdermal therapeutic system is at least 1.4.

10. The transdermal therapeutic system of claim 9 wherein said drug is selected from the group consisting of clonidine, scopolamine, propranolol, estradiol, phenylpropanolamine, ouabain, salbutamol, guanabenz, labetolol, atropine, haloperidol, bromocryptine, chloropheniramine, metrifonate, isosorbide dinitrate and nitroglycerin.

11. The system of Claim 9 wherein said drug is clonidine and the in vitro drug release rate from the system to an infinite sink is at least 2.0 µg/cm2 hr.

12. In a drug containing matrix composition consisting of a gel of miner-al oil and polyisobutylene having a moderately mineral oil-soluble drug dispersed therethrough, the improvement wherein said composition has at least about 5.0%
colloidal silicon dioxide dispersed therethrough, a mineral oil/polyisobutylene ratio of at least 1.0 and a viscosity of at least about 1.5 x 107 poise.

13. The matrix composition of Claim 11 wherein said mineral oil/poly-isobutylene ratio is at least about 1.2, the colloidal silicon dioxide is present in amounts of between 6 and 10% and said drug is present in an amount no less than saturation concentration and no greater than about 40%.

14. The composition of claim 12 wherein said drug is clonidine and the permeability of the matrix to clonidine is at least 1 x 10-4 µg/cm sec.