WO2013086731A1

WO2013086731A1 - Delivery apparatus

Info

Publication number: WO2013086731A1
Application number: PCT/CN2011/084106
Authority: WO
Inventors: Christopher BRANFORD- WHITE; Limin Zhu; Deng-guang YU
Original assignee: LONDON METROPOLITAN UNIVERSITY (LMU)
Current assignee: LONDON METROPOLITAN UNIVERSITY (LMU)
Priority date: 2011-12-16
Filing date: 2011-12-16
Publication date: 2013-06-20
Anticipated expiration: 2014-06-16

Abstract

Composite nanofibres (1) are disclosed, having two connected dissimilar polymer strands (2, 3). Each of the strands (2, 3) has at least of a portion of its surface (5, 6) exposed on the surface of the composite nanofibre (1). Apparatus for forming such nanofibres is also disclosed, in the form of a spinneret (7) having inclined channels (8, 11).

Description

DELIVERY APPARATUS

Field of the Invention The invention relates to delivery devices for contacting active ingredients, especially pharmaceuticals, with the surface of a patient's skin, and particularly those devices intended for transdermal drug delivery.

Background and Prior Art Known to the Applicant

Transdermal drug delivery is known in the art, with pharmaceuticals delivered by the transdermal route through application of drug-impregnated "patches" that may be affixed to a patient's skin. Examples of such drug delivery include nicotine to aid smoking cessation, as well as opioids such as fentanyl and buprenorphine for continual pain relief, scopolamine for the treatment of motion sickness and estrogen for treatment of menopausal symptoms.

An advantage of these transdermal drug delivery systems (TDDS) is that the patch provides a controlled release of the medication into the patient, usually via a porous membrane surrounding the reservoir of drug in the patch. Transdermal drug delivery was described by Prausnitz and Langer in Nature Biotechnology, 2008, 26, 1261-1268.

Although a wide variety of pharmaceuticals are available in transdermal patch form, the main problem for efficient TDDS stems from the fact that the skin is a very effective barrier. New methods of improved delivery focus on increasing the drug release rate and sustained release time to optimize transdermal drug therapy.

Of the different methods of producing transdermal patches, eletrospun nanofibre mats have attracted increasing interest for developing new TDDS due to their unique characteristics, including: (1) a high porosity with a very small pore size resulting from their three-dimensional continuous web structure; (2) a very small fibre diameter (typically having a diameter of less than about 1 micron) and a correspondingly very large surface area; (3) a relatively simple manufacturing process; (4) the ability to include excipients within composite nanofibres; (5) a choice of pharmaceutically-acceptable polymers from which to form the fibres; (6) the presence of nanometre-scale structures which lead to favourable clinical outcomes for drug transfer combined with the macroscopic structure of the mats that allows easy processing, stability, ease of shipping and application found with "conventional" transdermal patch structures.

However, one of the difficulties of electrospun nanofibre mats is a critical problem of adhesion to the skin - a factor that is important in the safety, efficacy and quality of any TDDS product. In its Drug Quality Reporting System (DQRS) the United States Food and Drug Administration (FDA) has received numerous reports of "adhesion lacking" in new transdermal drug delivery systems. Such poor adhesion could potentially lead to delivery of inadequate doses to patients, the need to replace patches more often. This can increase costs, and lead to safety issues.

Electrospun nanofibres can be "functionalized" (i.e. given specific capabilities such as drug-delivery) by the incorporation of functional molecules or building blocks in the filament-forming polymer matrix during their manufacture. However, it is difficult to find polymer fibres that can provide both good, sustained drug release in addition to having good bioadhesive performance as well. Although in principle, it might be possible to produce nanofibres that combine different types of polymers in a single electrospinning process to produce drug-loaded fibres with multiple desired functions, in practice the problem is complex. Particular problems are: compatibility of the drug, solvent and polymers for successful electropinning; whether or not the polymers are thermo dynamically miscible; thermodynamic and kinetic aspects of mixing; and the behaviour of the functional materials when dissolved in solution.

Nanofibres have been shown to have valuable properties for assisting graft implantation, cellular proliferation, cellular alignment and therefore functionality of cell therapies. For example, aligned nanofibres have been shown to help promote neurite outgrowth for nerve repair.

Co-axial two-component nanofibres are also known. It is amongst the objects of the invention to attempt a solution to these problems.

Summary of the Invention One way to avoid these complex issues is to electrospin two polymers simultaneously in a side-by-side fashion. In this case, the two polymer solutions do not come into physical contact with each other until they reach the end of the spinneret where the process of fibre formation begins. This allows the functional ingredients to be dissolved in different solution systems for easy preparation of muti- functional nanofibres.

Accordingly, the invention provides a nanofibre comprising two connected dissimilar polymer strands, each of said strands having at least a portion of its surface exposed on the surface of said nanofibre. Preferably, said strands lie adjacent each other, and more preferably said strands are connected along the majority of their length. In preferred embodiments the polymers of each strand are dissimilar.

On one of the strands a filament- forming bioadhesive polymer may be used, such as polyethylene oxide (PEO), hydroxypropyl methyl cellulose (HPMC), chitosan, gelatin, carboxymethyl cellulose (CMC) such as Na-CMC and Xanthan gum.

Preferably, therefore, one of said strands comprises an adhesive polymer.

The other strand can be prepared from solutions of the active ingredient (such as a drug) and a polymer matrix tailored to achieve optimal sustained drug release profiles of the active pharmaceutical ingredients (API). Traditional polymer excipients used in pharmaceutical applications, biodegradable polymers and some man-made polymers are suitable. Such polymers include PLA (polylactic acid), PLGA (poly(lactic-co-glycolic acid)), PCL (polycaprolactone) and EVOH (Ethylene Vinyl Alcohol). One of said strands, therefore, preferably comprises a diffusible active ingredient.

A transdermal penetration enhancer may also be incorporated into one of the strands. In any aspect, the invention provides a nanofibre as described herein in which one of said strands comprises an adhesive polymer and the other (if there are two strands) or another (if there are more than two strands) said strand comprises a polymer containing a diffusible active ingredient.

Preferably, said active ingredient comprises a medicament.

The invention also provides a device for use in a method of transdermal delivery of a medicament comprising a mat of nanofibres as described herein. In preferred embodiments, said device further comprises a cover on one side of said mat.

In a further related aspect, the invention also provides apparatus for forming nanofibres as described herein. Specifically, the invention provides apparatus for forming a nanofiber described herein comprising a spinneret having: a first fluid channel for fluid delivery of a first polymer composition; a second fluid channel for fluid delivery of a second polymer composition; said channels each having an inlet and an outlet, the said outlets being arranged adjacent each other; and wherein the longitudinal axes of said channels are arranged to be angled towards each other at the outlet of each channel.

Preferably, the angle between said channels is between 5 and 80 degrees, more preferably between 20 and 80 degrees, and most preferably between 45 and 70 degrees. More generally, the minimum angle between said channels should be 5, 10, 15, 20, 25 of 30 degrees, and the maximum angle should be 80, 75, 70, 65, or 60 degrees. The inventors have found that these ranges of angles provide stability in dual nanofibre formation.

Preferably also, said outlets are spaced apart by less than 1mm. Brief Description of the Drawings The invention will be described by with reference to the accompanying drawings, in which:

Figures 1 and 2 illustrate respective transverse and longitudinal cross-sections of embodiments of nano fibres of the present invention;

Figures 3 and 4 illustrate cross-sections of embodiments of spinnerets of the present invention;

Figure 5 illustrates an electrospinning apparatus using a spinneret of the present invention; and

Figure 6 illustrates a drug delivery device of the present invention. Description of Preferred Embodiments

Figure 1 illustrates a transverse cross-section of a nanofibre of the present invention, generally indicated by 1. The nanofibre is formed from two connected polymer strands (2, 3), each strand being formed of a different polymer composition. The strands 2, 3 are connected along longitudinal edges at a mid-region 4 of the nanofibre. The mid-region of the nanofibre may contain a mixture of the two polymer compositions. Figure 2 illustrates a longitudinal cross-section of a short portion of the nanofibre of Figure 1, illustrating that the two strands 2, 3 forming the composite nanofibre 1 lie adjacent each other. The strands are connected to each other along the majority of their length, and at least a portion of the surface 5, 6 of each strand 2, 3 is exposed on the surface of the nanofibre 1.

A typical width, w, of the nanofibres is less than 1 micron, most preferably about 500nm, in the range of 50 to 1000 nm.

In preferred embodiments, the composition of one of the strands 2 comprises a filament- forming bioadhesive polymer such as polyethylene oxide (PEO), hydroxypropyl methyl cellulose (HPMC), chitosan gelatin, carboxymethyl cellulose (CMC) such as Na-CMC and Xanthan gum. Example formulations and methods for preparing nanofibres of the present invention are described below.

Figure 3 illustrates a cross-sectional view of a second aspect of the invention, being a spinneret suitable for producing nanofibres of the first aspect of the invention. The spinneret, generally indicated by 7, comprises a first fluid channel (e.g. a tube, or conduit) 8 having an inlet 9 and an outlet 10 and a second fluid channel 11 having an inlet 12 and an outlet 13. The two outlets 10, 13 are arranged to discharge adjacent each other at a separation, X, of typically less than 1mm, as illustrated in Figure 4. As the channels 8, 11 approach the fluid exits 10, 13, the respective longitudinal axes 14, 15 of each channel are arranged to be angled towards each other such that during an electrospinning process using the spinneret, polymer compositions pumped through the respective channels impact on each other and coalesce to form a composite nanofibre of the first aspect of the present invention.

The angle Φ between the axes 14, 15 of the channels is preferably between 20 and 70 degrees.

In preferred embodiments of the spinneret, the two exit channels are mounted independently of each other on movable supports, such that the separation and relative angular inclination of the exit channels may be varied to suit different polymer compositions.

Figure 5 illustrates a typical configuration of an electrospinning apparatus, generally indicated by 16, and comprising a spinneret 7 of the invention and an electrically conductive collector plate 17. The spinneret 7 is preferably made of electrically- conductive material, such as stainless steel.

In operation, a high voltage (AV) is applied between the spinneret 7 and the collector plate 17. A voltage of several kilo Volts (e.g. around 15kV) is typical for spinneret - collector plate separations of the order of 20cm. Appropriate voltages and separations may be determined by those skilled in the art of electrospinning, generally. Two polymer solutions are passed through the spinneret by means of a pump (not illustrated). The first polymer solution is passed through exit nozzle 10 via inlet 9, and the second solution through exit nozzle 13 via inlet 12. The potential difference between the emerging polymer streams and the collector plate causes the streams to accelerate towards the plate (as indicated by the arrow), with a consequent thinning of the strands. The strands coalesce due to the angle of the exit channels, and a composite nanofibre of the present invention is formed.

Figure 6 illustrates a medicament delivery device, generally indicated by 18, comprising a mat of nano fibres 19 secured to a cover 20. The cover has adhesive regions 21 around the mat 19, allowing the device to be secured to a patient's skin, thereby pressing the mat against the skin surface. The high surface area of the nanofibres facilitates diffusion of medicament contained within the nanofibres to the skin surface, for transdermal delivery. The inclusion of a biocompatible adhesive polymer within at least one strand of the nanofibres ensures close and continuing contact of the nanofibres with the skin.

Example 1

Side-by-side electro-spinning for step-by-step self-assembly drug delivery systems Materials: Filament- forming matrix polymers polyvinylpyrrolidone K60 (PVP K60, with a molecular weight of ca. 360,000 Da) was purchased from BASF Corp. (Shanghai, China). Methacrylic acid copolymer (Eudragit LI 00) was obtained from Rohm Pharma (Weiterstadt, Germany). Diclofenac sodium (DS) was purchased from Shanghai Pharmaceutical Co., Ltd. (Shanghai, China), paste lecithin (PL, extracted from egg yolks) was provided by the Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Analytical grade anhydrous ethanol, methanol and N, N-dimethylacetamide (DMAc) were obtained from the Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China).

Electro- spinning processes: In this example, two polymer solutions were used for side- by side electrospinning. The first polymer composition consisted of 1%:5%: 15% (w/v) of DS, PL and Eudragit in a mixed solvent of DMAc and methanol with a volume ratio of 80:20. The second polymer composition consisted of 0.8%:4%: 10% (w/v) of DS, PL and PVP K60 in ethanol. The polymer solutions were degassed with a SK5200H ultrasonicator (350W, Shanghai Jinghong Instrument Co., Ltd. (Shanghai, China) for 15 min before the spinning processes. A high voltage power supply (Shanghai Sute Electrical Co., Ltd) was used to provide high voltages in the range of 0-60 kV. The positive electrode of the high voltage power supply was connected to a "side-by-side" spinneret of the present invention, and made of stainless steel. The grounded electrode was connected to a metal collector wrapped with aluminium foil. The feed rate of two polymer solutions through the two fluid channels of the spinneret was controlled by means of two syringe infusion pumps (KDS 100, Cole- Parmer®, USA). Formed fibers were dried for over 24 h at 40 °C under vacuum (320 Pa) in a DZF-6050 electric vacuum drying oven (Shanghai Laboratory Instrument Work Co. Ltd, Shanghai, China) to facilitate the removal of residual organic solvent and moisture.

For the electrospinning, the applied high voltage was 15 kV and the flow rate of each polymer solution through the spinneret was 1.0 mL/h. The fibre-collected distance (the distance between the spinneret and the collector plate) was fixed at 20cm. The electrospinning process was conducted under ambient conditions.

The morphology of the surface and the cross-sections of the nano-fiber mats were assessed using a S-4800 field emission scanning electron microscope (Hitachi, Japan). The average fiber diameter was determined by measuring diameters of composite nano- fibers over 100 points from FESEM images using Image J software (National Institutes of Health, USA). The fibre illustrated has a width of approximately 550 nm.

Example 2

Side-by-side electro-spinning for effective transdermal drug delivery systems

Materials: Filament- forming matrix polymers polyvinylpyrrolidone K60 (PVP K60, having a molecular weight of ca. 360,000 Da) was purchased from BASF Corp. (Shanghai, China). Poly(ethylene oxide) (PEO, M_w =1000,000 Da) was purchased from the Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Cellulose acetate (CA, white powder; MW = 100,000 Da) was purchased from Acros, and used as received. Ibuprofen (IBU) and borneol were purchased from Shanghai Pharmaceutical Co., Ltd. (Shanghai, China). Analytical grade anhydrous ethanol, acetone and N, N- dimethylacetamide (DM Ac) were obtained from the Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China) and water was distilled just before use.

Electro- spinning processes: Again, two different polymer compositions were employed in the electrospinning process. The first polymer composition consisted of 0.5%:2%:6% (w/v) borneol, PEO and PVP in a mixed solvent of water and methanol with a volume ratio of 80:20. The second polymer composition consisted of 5%: 15% (w/v) of IBU, CA in a mixed solvent of acetone, ethanol and DM Ac with a volume ratio of 3 : 1 : 1. The polymer solutions were degassed with a SK5200H ultrasonicator (350W, Shanghai Jinghong Instrument Co., Ltd. (Shanghai, China) for 15 min before the spinning processes. A high voltage power supply (Shanghai Sute Electrical Co., Ltd) was used to provide high voltages in the range of 0-60 kV. The positive electrode of the high voltage power supply was connected to a side-by-side spinneret according to the first aspect of the invention, made of stainless steel. The grounded electrode was connected to a metal collector wrapped with aluminium foil. The feed rate of two polymer solutions through the spinneret was controlled by means of two syringe infusion pumps (KDS 100, Cole- Parmer®, USA). Formed fibres were dried for over 24 h at 40 °C under vacuum (320 Pa) in a DZF-6050 electric vacuum drying oven (Shanghai Laboratory Instrument Work Co. Ltd, Shanghai, China) to facilitate the removal of residual organic solvent and moisture.

In this instance the applied high voltage between the spinneret and the collector plate was 12 kV and the flow rate of each polymer composition through the spinneret was 1.0 mL/h. Fibres were collected at a fixed distance of 15cm between the spinneret and the metal collector plate. The electro-spinning process was conducted under ambient condition.

Characterization: The morphology of the surface and the cross-sections of the nano fiber mats were assessed using a S-4800 field emission scanning electron microscope - FESEM (Hitachi, Japan). Before carbon coating, the cross-sections of the nanofiber mats were prepared by placing them into liquid nitrogen for over 15 minutes, and then they were broken manually. The fibres' average estimated width is 375 ± 77 nm (n=22), and the diameters are 145 ± 50 nm and 110 ± 35 nm for the thicker and thinner component fibres respectively (n = 9). Transmission electron microscopy (TEM) images of the samples were taken on a JEM 21 OOF field-emission transmission electron microscope (JEOL, Japan). The side-by-side nano-fibers were collected on a carbon coated thin film on 200 mesh copper grids directly for TEM sampling. The fibres had the morphology as illustrated in Figs 1 and 2.

Claims

1. A nano fibre comprising two connected dissimilar polymer strands, each of said strands having at least a portion of its surface exposed on the surface of said nano fibre.

2. A nanofibre according to claim 1 wherein said strands lie adjacent each other.

3. A nanofibre according to Claim 1 or Claim 2 wherein said strands are connected along the majority of their length.

4. A nanofibre according to any preceding claim wherein the polymers of each strand are dissimilar.

5. A nanofibre according to any preceding claim wherein one of said strands comprises an adhesive polymer.

6. A nanofibre according to any preceding claim comprising a diffusible active ingredient.

7. A nanofibre according to any preceding claim in which one of said strands comprises an adhesive polymer and the other or another said strand comprises a polymer containing a diffusible active ingredient.

8. A nanofibre according to any preceding claim further comprising a transdermal penetration enhancer.

9. A nanofibre according to any of claims 6 to 8 wherein said active ingredient comprises a medicament.

10. A device for use in a method of transdermal delivery of a medicament comprising a mat of nanofibres according to claim 9.

11. A device according to claim 10 further comprising a cover on one side of said mat.

12. Apparatus for forming a nanofiber according to any of claims 1 to 9 or for forming apparatus according to either of claims 10 and 11 comprising a spinneret having:

a first fluid channel for fluid delivery of a first polymer composition;

a second fluid channel for fluid delivery of a second polymer composition;

said channels each having an inlet and an outlet, the said outlets being arranged adjacent each other;

and wherein the longitudinal axes of said channels are arranged to be angled towards each other at the outlet of each channel.

13. Apparatus according to claim 12 wherein the angle between said channels is between 5 and 80 degrees.

14. Apparatus according to either claim 12 or claim 13 wherein said outlets are spaced apart by less than 1mm.

15. A nano fibre substantially as described herein with reference to and as illustrated by any appropriate combination of the accompanying drawings.

16. A device for use in a method of transdermal delivery of a medicament substantially as described herein with reference to and as illustrated by any appropriate combination of the accompanying drawings.

17. Apparatus substantially as described herein with reference to and as illustrated by any appropriate combination of the accompanying drawings.