Method for making medicinal delivery device having multi-layer coating

Abstract

Methods of making components for a medicinal delivery device are described, in which a base composition comprising a polysulphone is applied to the surface of a component to create a base layer, a primer composition comprising a silane having two or more reactive silane groups separated by an organic linker group is applied to the base layer to create primed surface, and a coating composition comprising an at least partially fluorinated compound is applied to the primed surface. Corresponding coated components and a medicinal delivery device are disclosed.

Claims

1. A method of making a component for a medicinal delivery device, the method comprising: a) providing a component of a medicinal delivery device, b) providing a base composition comprising a polysulphone, c) providing a primer composition comprising a silane having two or more reactive silane groups separated by an organic linker group, d) providing a coating composition comprising an at least partially fluorinated compound, e) applying the base composition to at least a portion of the surface of the component, f) applying the primer composition to at least a portion of the surface of the component after the application of the base composition, and g) applying the coating composition to the portion of the surface of the component after application of the primer composition.

2. A method as claimed in claim 1, wherein the silane having two or more reactive silane groups is of formula:
X.sub.3-m(R.sup.1).sub.mSi-Q-Si(R.sup.2).sub.kX.sub.3-k wherein R.sup.1 and R.sup.2 are independently selected univalent groups, X is a hydrolysable or hydroxy group, m and k are independently 0, 1, or 2, and Q is a divalent organic linking group.

3. A method as claimed in claim 2, wherein Q is of formula —(CH.sub.2).sub.i-A-(CH.sub.2).sub.j— wherein A is NR.sup.n, O, or S, i and j are independently 0, 1, 2, 3, or 4, and wherein R.sup.n is H or C.sub.1 to C.sub.4 alkyl.

4. A method as claimed in claim 1, wherein the at least partially fluorinated compound is a polyfluoropolyether silane of formula:
R.sup.fQ.sup.1.sub.v[Q.sup.2.sub.w-[C(R.sup.4).sub.2—Si(X).sub.3-x(R.sup.5).sub.x].sub.3].sub.z wherein: R.sup.f is a polyfluoropolyether moiety; Q.sup.1 is a trivalent linking group; each Q.sup.2 is an independently selected organic divalent or trivalent linking group; each R.sup.4 is independently hydrogen or a C.sub.1-4 alkyl group; each X is independently a hydrolysable or hydroxyl group; R.sup.5 is a C.sub.1-8 alkyl or phenyl group; v and w are independently 0 or 1, x is 0 or 1 or 2; y is 1 or 2; and z is 1, 2, 3, or 4.

5. A method as claimed in claim 4, wherein the polyfluoropolyether moiety R.sup.f comprises perfluorinated repeating units selected from the group consisting of —(C.sub.nF.sub.2nO)—,—(CF(Z)O)—, —(CF(Z)C.sub.nF.sub.2nO)—, —(C.sub.nF.sub.2nCF(Z)O)—, —(CF.sub.2CF(Z)O)—, and combinations thereof; wherein n is an integer from 1 to 6 and Z is a perfluoroalkyl group, an oxygen-containing perfluoroalkyl group, a perfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy group, each of which can be linear, branched, or cyclic, and have 1 to 5 carbon atoms and up to 4 oxygen atoms when oxygen-containing or oxygen-substituted and wherein for repeating units including Z the number of carbon atoms in sequence is at most 6.

6. A method as referred in claim 5, wherein the number of linked perfluorinated repeating units is in the range 20 to 40.

7. A method as claimed in claim 1, wherein the base composition comprises a polyethersulphone.

8. A method as claimed in claim 1, wherein said surface is a metal surface selected from the group consisting of an aluminium alloy, an iron alloy, and a steel alloy.

9. A method as claimed in claim 1, where said medicinal delivery device is a metered dose inhaler or a dry powder inhaler.

10. A method as claimed in claim 1, wherein the component is a component of a metered dose inhaler and the component is selected from the group consisting of an actuator, an aerosol container, a ferrule, a valve body, a valve stem and a compression spring.

11. A medicinal delivery device assembled from at least one component made as claimed in claim 1.

12. A method as claimed in claim 1, wherein said portion of surface is a polymer surface.

13. A method of making a component for a medicinal delivery device, the method comprising a) providing a component of a medicinal delivery device, b) providing a coating composition comprising an at least partially fluorinated compound, c) providing a base composition comprising polyethersulphone in an amount of less than 20% by weight, d) applying the base composition to at least a portion of the surface of the component to provide a base layer, e) applying the coating composition to at least a portion of the surface of the component after application of the base layer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) So that the present specification may be more completely understood, reference is made to the accompanying drawings in which:

(2) FIG. 1a represents a schematic cross-sectional view of a pressurized metered dose inhaler known in the art and

(3) FIG. 1b represents an enlarged view of a portion of the inhaler.

(4) FIG. 2 represents a schematic cross-sectional view of a metered dose valve.

DETAILED DESCRIPTION

(5) FIG. 1a shows a metered dose inhaler 100, including an aerosol container 1 fitted with a metered dose valve 10 (shown in its resting position). The valve is typically affixed, i.e., crimped, onto the container via a cap or ferrule 11 (typically made of aluminium or an aluminium alloy) which is generally provided as part of the valve assembly. Between the container and the ferrule there may be one or more seals. In the embodiments shown in FIGS. 1a and 1b between the container 1 and the ferrule 11 there are two seals including e. g., an O-ring seal and the gasket seal.

(6) As shown in FIG. 1a, the container/valve dispenser is typically provided with an actuator 5 including an appropriate patient port 6, such as a mouthpiece. For administration to the nasal cavities the patient port is generally provided in an appropriate form (e.g., smaller diameter tube, often sloping upwardly) for delivery through the nose. Actuators are generally made of a plastics material, for example polypropylene or polyethylene. As can be seen from FIG. 1a, the inner walls 2 of the container and the outer walls 101 of the portion(s) of the metered dose valve located within the container define a formulation chamber 3 in which aerosol formulation 4 is contained.

(7) The valve shown in FIG. 1a, and FIG. 1b, includes a metering chamber 12, defined in part by an inner valve body 13, through which a valve stem 14 passes. The valve stem 14, which is biased outwardly by a compression spring 15, is in sliding sealing engagement with an inner tank seal 16 and an outer diaphragm seal 17. The valve also includes a second valve body 20 in the form of a bottle emptier. The inner valve body (also referred to as the “primary” valve body) defines in part the metering chamber. The second valve body (also referred to as the “secondary” valve body) defines in part a pre-metering region or chamber besides serving as a bottle emptier.

(8) Referring to FIG. 1b, aerosol formulation 4 can pass from the formulation chamber into a pre-metering chamber 22 provided between the secondary valve body 20 and the primary valve body 13 through an annular space 21 between the flange 23 of the secondary valve body 20 and the primary valve body 13. To actuate (fire) the valve, the valve stem 14 is pushed inwardly relative to the container from its resting position shown in FIGS. 1a and b, allowing formulation to pass from the metering chamber through a side hole 19 in the valve stem and through a stem outlet 24 to an actuator nozzle 7 then out to the patient. When the valve stem 14 is released, formulation enters into the valve, in particular into the pre-metering chamber 22, through the annular space 21 and thence from the pre-metering chamber through a groove 18 in the valve stem past the inner tank seal 16 into the metering chamber 12.

(9) FIG. 2 shows a metered dose aerosol valve different to the one shown in FIGS. 1a, 1b in its rest position. The valve has a metering chamber 112 defined in part by a metering tank 113 through which a stem 114 is biased outwardly by spring 115. The stem 114 is made in two parts that are push fit together before being assembled into the valve. The stem 114 has an inner seal 116 and an outer seal 117 disposed about it and forming sealing contact with the metering tank 113. A valve body 120 crimped into a ferrule 111 retains the aforementioned components in the valve. In use, formulation enters the metering chamber via orifices 121, 118. It's outward path from the metering chamber 112 when a dose is dispensed is via orifice 119.

(10) Depending on the particular metered dose valve and/or filling system, aerosol formulation may be filled into the container either by cold-filling (in which chilled formulation (chilled to temperatures of about −50 to −55° C. for propellant HFA 134a-based formulations) is filled into the container and subsequently the metered dose valve is crimped onto the container) or by pressure filling (in which the metered dose valve is crimped onto the container and then formulation is pressure filled through the valve into the container).

(11) Embodiments of the present invention is further illustrated by the following Examples.

EXAMPLES

(12) Fluorosilane A is a fluorosilane of formula:
(MeO).sub.3Si(CH.sub.2).sub.3OCH.sub.2CF(CF.sub.3)(OCF.sub.2CF(CF.sub.3)).sub.kO(CF.sub.2).sub.2CF.sub.3, in which k is approximately 34.

(13) BTMSPA refers to bis(trimethoxysilylpropyl)amine.

(14) Deposition Assay for Canisters

(15) Micronized, non-amorphous salbutamol sulphate that was ultrasonically dispersed in decafluoropentane (1 g in 400 g) was used as the drug deposition agent. Under ambient conditions, an aliquot of the salbutamol sulphate dispersion (0.3 mL) was instilled into each canister using a pipette and the canister was immediately placed on a horizontal rolling mixer (Stuart Scientific model SRT2 operating at 35 rpm) for three minutes to allow for the dispersion to dry to the surface of the canister. The canisters were then placed in a drying oven for five minutes at 65° C. The dried canisters were individually rinsed with two aliquots of fresh decafluoropentane (each 5 mL) using a five inversion manual shaking regime with one 180 degree shake cycle per second. After the final rinse, the canisters were inverted and then maintained for 15 minutes to allow residual decafluoropentane to evaporate.

(16) The salbutamol sulphate residue remaining in each canister was then assayed. This was performed by dispensing 10 mL of acidified water (deionised water to which 10 mL of 0.1N HCl was added for each 1 liter of deionised water) into each canister. Each canister was capped and then inverted three times to effect dissolution of the salbutamol sulphate residue. The solution in each canister was then assayed using a UV Spectrophotometer (model Lambda 20, PerkinElmer Corporation, Waltham, Mass.) fitted with a sipper cell to sample the solution directly from the canister. Absorbance measurements of the solutions were taken at 276 nm.

(17) Control canisters were prepared from washed, uncoated aluminium canisters. The salbutamol sulphate dispersion was added and dried (as described above), but for the control canisters the rinse step was eliminated. Consequently, the control canisters had a deposited amount of salbutamol sulphate that represented the maximum amount possible for the assay.

(18) Coated canisters that had a low level of salbutamol sulphate deposition following the rinse step were deemed to have a coating with good release/non-stick performance.

(19) The amount of salbutamol sulphate measured for each canister was divided by the corresponding amount measured for the control canisters and the result was expressed as a percentage. Unless otherwise stated, the mean percentage was determined using the results from three canisters.

Example 1

(20) Washing of Canisters

(21) Aluminum canisters (16 mL, used as containers in metered dose inhalers and available from the 3M Company, Clitheroe, UK) were immersed in NOVEC HFE-72DE engineered fluid (a blend of methyl and ethyl nonafluorobutyl ethers with trans-1,2-dichloroethylene, available from the 3M Company, St. Paul, Minn.) at its boiling temperature (43° C.) for seven minutes. The canisters were inverted, drained for two minutes, and then re-immersed in the boiling HFE-72DE for three minutes with added ultrasonic agitation. Next, the canisters were inverted, drained for four minutes, and then air dried for seven minutes.

(22) Preparation of Coated Canisters

(23) Washed aluminium canisters were filled to the brim with a 13 weight percent solution of polyethersulphone (Veradel A-304 NT, available from Solvay Speciality Polymers, Belgium) in cyclopentanone, maintained in the filled state for 60 seconds, and then inverted for five minutes to drain the coating solution. The coated canisters were air dried and then placed in an oven for 30 minutes at 120° C.

(24) The resulting polyethersulphone coated canisters were cooled to 21° C. and then filled to the brim with primer solution (0.1 g of BTMSPA in 84 g of NOVEC HFE-72DE). The canisters were maintained in the filled state for 30 seconds and then inverted to drain the liquid. The canisters were air dried and then placed in an oven for 30 minutes at 140° C.

(25) The resulting primer coated canisters were equilibrated to ambient temperature and humidity, and then filled to the brim with a 0.2 weight percent solution of Fluorosilane A in NOVEC 7200 (a hydrofluoroether solvent blend available from the 3M Company, St. Paul, Minn.). The canisters were maintained in the filled state for 30 seconds and then inverted to drain the liquid. The canisters were air dried and then placed in an oven for 30 minutes at 140° C. The canisters were cooled to ambient temperature and stored under ambient conditions in a resealable polythene bag.

(26) Deposition Assay

(27) The deposition assay was conducted as described above for the canisters prepared according to Example 1. As a comparator, aluminum canisters that were washed, but not coated were also submitted to the deposition test. The results are presented in Table 1.

(28) TABLE-US-00001 TABLE 1 Mean Percent Deposition of Salbutamol Sulphate Canister Type Relative to Control Canisters Coated Canisters of Example 1 0.33% Washed\Uncoated Canisters 94.7%

Example 2

(29) Washing of Canisters

(30) Washed 16 mL aluminium canisters were prepared using the washing procedure described in Example 1.

(31) Preparation of Coated Canisters

(32) Washed aluminium canisters were filled to the brim with a 5 weight percent solution of polyphenylsulphone (Radel R5000 NT, available from Solvay Speciality Polymers, Belgium) in cyclopentanone, maintained in the filled state for 60 seconds, and then inverted for 60 seconds to drain the coating solution. The coated canisters were dried by rolling for 16 hours on a horizontal, rolling mixer.

(33) The resulting polyphenylsulphone coated canisters were filled to the brim with primer solution (0.5 g of BTMSPA in 84 g of NOVEC HFE-72DE). The canisters were maintained in the filled state for 30 seconds and then inverted to drain the liquid. The canisters were air dried and then placed in an oven for 30 minutes at 140° C.

(34) The resulting primer coated canisters were filled to the brim with a 0.2 weight percent solution of Fluorosilane A in NOVEC 7200. The canisters were maintained in the filled state for 30 seconds and then inverted to drain the liquid. The canisters were air dried and then placed in an oven for 30 minutes at 140° C. The canisters were cooled to ambient temperature and stored under ambient conditions in a resealable polythene bag.

(35) Deposition Assay

(36) The deposition assay was conducted as described above for the canisters prepared according to Example 2. As a comparator, aluminum canisters that were washed, but not coated were also submitted to the deposition test. The results are presented in Table 2.

(37) TABLE-US-00002 TABLE 2 Mean Percent Deposition of Salbutamol Sulphate Relative Canister Type to Control Canisters Coated Canisters of Example 2  3% Washed\Uncoated Canisters 95%

Example 3

(38) Coated canisters prepared according to Example 1 and washed/uncoated aluminum canisters (comparator canisters) were equilibrated for one hour in environmental chambers that were held at a selected temperature and relative humidity (RH). The deposition assay (as described above) was conducted in the environmental chamber. Some of the washed/uncoated canisters were treated according to the procedure for control canisters. Following the rinsing step, canisters were removed from the chamber and assayed using the UV spectrophotometry procedure described above. The results are presented in Table 3 with the mean percent deposition calculated using the results from five canisters.

(39) TABLE-US-00003 TABLE 3 Mean Percent Deposition of Salbutamol Environmental Sulphate Relative to Control Canisters Chamber Coated Canisters Washed\Uncoated Conditions of Example 1 Canisters 21° C., 25% RH 1% 65% 21° C., 35% RH 1% 69% 21° C., 45% RH 1% 77% 21° C., 55% RH 1% 89% 21° C., 65% RH 5% 92%

(40) The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.