WO1989010740A1 - Buccal local anaesthetic - Google Patents

Buccal local anaesthetic Download PDF

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Publication number
WO1989010740A1
WO1989010740A1 PCT/GB1989/000491 GB8900491W WO8910740A1 WO 1989010740 A1 WO1989010740 A1 WO 1989010740A1 GB 8900491 W GB8900491 W GB 8900491W WO 8910740 A1 WO8910740 A1 WO 8910740A1
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WO
WIPO (PCT)
Prior art keywords
anaesthetic
patch
lidocaine
film
polymer matrix
Prior art date
Application number
PCT/GB1989/000491
Other languages
French (fr)
Inventor
Robert Nichol Boyes
Brenda Perkins
Janna N. Strobel
Richard L. Dunn
Original Assignee
Innovata Biomed Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GB888810951A priority Critical patent/GB8810951D0/en
Priority to GB8810951.7 priority
Application filed by Innovata Biomed Limited filed Critical Innovata Biomed Limited
Publication of WO1989010740A1 publication Critical patent/WO1989010740A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Abstract

An anaesthetic patch suitable for use in the mouth is disclosed, which comprises a biocompatible hydrophilic polymer matrix loaded with an anaesthetic, which matrix is capable of adhering directly to the oral mucosa without an adhesive, and an impermeable inert support membrane.

Description

BUCCAL LOCAL ANAESTHETIC

This invention relates to an anaesthetic patch for use in the mouth.

Local anaesthesia for dental procedures is usually provided by parenteral injection of a suitable local anaesthetic product such as lignocaine or prilocaine. In some cases, these drugs are formulated in ointments, creams, gels or aerosol sprays to be applied to the gums to provide local pain relief. All of these anaesthetic procedures have significant disadvantages from both a medical and a patient acceptance point of view. Parenteral injections are difficult to administer, are extremely uncomfortable for the patient, are occasionally associated with serious adverse reactions and, in general, the anaesthesia lasts for a prolonged period after the dental procedure, causing unpleasant numbness in the lips and tongue of the patient. The various topical products are rapidly removed from their site of application in the mouth by the saliva and, as a result, the duration of their effect is very short. Furthermore, the anaesthetic is free to diffuse throughout the mouth and, thereby, causes an unpleasant taste as well as discomforting numbness in the tongue.

According to the present invention there is provided an anaesthetic patch for use in the mouth, which patch comprises a film comprising a biocompatible, hydrophilic polymer matrix loaded with an anaesthetic, which matrix is capable of adhering directly to the oral mucosa without an adhesive and an impermeable inert support membrane.

Optionally the anaesthetic patch includes a third component in the form of a release liner, which is positioned over the loaded matrix to keep the matrix clean prior to use of the patch. This liner is removed immediately before application of the patch to the oral mucosa.

Typically the release liner comprises silicone treated paper.

It is therefore possible in accordance with the invention to provide a device which concentrates the local anaesthetic to a specific site on the gums and which does not allow drug to diffuse into the mouth in general. The patch may not only provide concentrated anaesthetic effect to the site of application but that effect can also continue until the device is removed. The patch may allow anaesthetic agent to penetrate the gingival mucosa and reach the nerves which transmit painful stimuli from the tooth. The patch can therefore be employed to provide anaesthesia for operative procedures of the gums as well as for restorative procedures of the teeth themselves.

The patch incorporates a film comprising a biocompatible, hydrophilic polymer matrix loaded with anaesthetic. The film should have good adhesive properties, i.e. good wet tack, as the patch must adhere directly to the oral mucosa through the surface of the film not provided with a backing material. Wet tack may be determined by pressing a moist finger onto the surface of the film and then observing the adhesion of the film to the finger.

Suitable polymers for the matrix include sodium carboxymethyl cellulose (CMC), poly(vinyl pyrrolidone) (PVP), copolymers of methyl vinyl ether and maleic anhydride such as Gantrez (trade mark) ES-225 and an acrylic latex such as Rhoplex (trade mark) NB-560. Preferred polymers are polymers from which soft and flexible films may be formed. Such films are most practical for use in the mouth. Preferred polymers are therefore PVP and copolymers of methyl vinyl ether and maleic anhydride. PVP's are generally used having molecular weights from 20000 to 700000, typically from 40000 to 360000, for example PVP-40, PVP K-60 and PVP K-90 having molecular weights of 40000, 160000 and 360000 respectively. The low molecular weight PVP K-29/32 (having a molecular weight of in the region of 30000) may also be used. Although polymers of lower molecular weight have the potential to impart greater flexibility to the patch than those of higher molecular weight, PVP K-90 combines a satisfactory degree of flexibility with strength and is therefore particularly suitable.

A non-toxic plasticiser may be incorporated into the polymer matrix to improve the softness and flexibility of the final patch. Suitable plasticisers include sorbitol and glycerol. Glycerol is generally preferred since it has a higher solubility in the solvents used in the preparation of the anaesthetic-loaded patch. The plasticiser may be incorporated in any amount, within the limits of its solubility, and is typically used in an amount of from 0.01 to 15% of the total weight of the anaesthetic-loaded matrix. For example, sorbitol is suitably used in an amount of 0.5% by weight and glycerol is suitably used in an amount of 5% by weight.

When the polymer matrix of the patch comprises more than one polymer, for example two, it is possible for the second polymer to act as a plasticiser within the composition. One example of a patch within the invention comprises a polymer matrix consisting of the anaesthetic lidocaine, two PVP's (PVP K-90 and PVP K-29/32) and glycerol in a weight ratio of 25:45:25:5. The PVP K-29/32, having a lower molecular weight than the PVP K-90, acts as a plasticiser in addition to the glycerol.

The anaesthetic provided in the patch may be a local anaesthetic, although the patches can be employed to deliver systemic anaesthetics too. An amide anaesthetic may be employed such as lignocaine (lidocaine), prilocaine, carbocaine, bupivacaine or etidocaine. The anaesthetic may be employed in free form or in the form of an acid addition salt, typically the hydrochloride. In particular, lignocaine or lignocaine hydrochloride is used.

The support membrane of the patch is inert and impermeable. The membrane generally comprises polyurethane, for example it is a polyester/polyurethane film or foam, and is typically coated with an acrylic adhesive. The anaesthetic-loaded polymer matrix adheres in this case to the acrylic adhesive coating which, in turn, is relatively impermeable to the anaesthetic. The side of the membrane opposite to that coated with adhesive presents a smooth, non-sticky surface to the oral cavity, protecting and supporting the patch as a whole. The support membrane may be formed by laminating an acrylic adhesive, such as TT5022-00 available from Semex Medical, Frazer PA, US to a polyurethane which is in the form either of a thin film or a slightly thicker foam. A maximum thickness for the polyurethane film is generally about 63.6 μm (2.5 mil) whereas for the foam the maximum thickness is generally 762μm (30 mil).

Alternatively a commercially available support membrane may be used. Particularly suitable is KM1354-00, from Semex Medical, a polyester/polyurethane film coated with an acrylic adhesive. This typically comes provided with a silicone-treated release liner which protects the adhesive side of the membrane. A further example of a suitable membrane is KM-1952, an acrylic adhesive/polyurethane foam also from Semex Medical.

The support membrane is impermeable so that water and saliva can not penetrate into the patch and thereby allow anaesthetic to leach out through the surface which does not adhere to the oral mucosa. The support membrane is therefore typically coterminous in area with the polymer matrix film loaded with anaesthetic. This has the additional effect of ensuring a unidirectional flow of anaesthetic into the tissue of the mouth to be anaesthetised.

The third, and optional, component in the patch of the present invention is a release liner which is placed over the anaesthetic-loaded matrix. The liner serves both to keep the matrix clean and to prevent individual patches from adhering to each other when packaged. The liner is typically a silicone-treated paper and a suitable example is 3402 available from Semex Medical, Frazer, PA. This particular product comes provided with a support membrane, although it is not essential to the invention that the release liner be supplied together with a support membrane.

The anaesthetic is suitably incorporated in the polymer matrix in an amount of from 1 to 30% by weight. The proportions may vary in this range depending upon the type of anaesthesia it is desired to induce. For anaesthesia of soft tissue, therefore, the film typically incorporates from 2 to 15% by weight of anaesthetic. For anaesthesia of deep tissue, the film typically comprises from 15 to 25% by weight of anaesthetic. The amount of anaesthetic will also depend upon the potency of the anaesthetic, however. For lignocaine either as the free base or as the hydrochloride, for example, from 5 to 30 mg of anaesthetic may be incorporated per cm2 of the surface area of a patch.

The patches of the invention are suitably prepared by casting. In a preferred method, which is both economical and continuous, a doctor blade is used. This method comprises dissolving the anaesthetic and the matrix polymer in an appropriate inert solvent such as water, ethanol or acetic acid. Ethanol is particularly suitable. The resulting solution is then placed at one end of a casting substrate and a doctor blade is moved across the solution for the length of the casting substrate to spread the solvent blend evenly over the casting substrate. The solvent then evaporates off.

The casting substrate may be either the support membrane itself or, alternatively, the release liner. It is particularly convenient to use the release liner as casting substrate and to attach the support membrane to the polymer matrix charged with anaesthetic in a subsequent step to form a complete patch.

The doctor blade used in this casting method may be any length, for example about 20 cm (or approx 8 in). The height of the blade is generally adjustable. Altering the weight has the effect of varying the thickness of the film formed on the casting substrate. The thickness of the film contributes to determining the content of anaesthetic in the final patch.

Besides adjusting the height of the doctor blade, an alternative means of controlling the thickness of the film on the casting substrate is by adjusting the viscosity of the casting solution. This may be done, for example by varying the content of ethanol in the solution.

The softness and flexibility of the final patch is increased by incorporating one or more plasticisers into the casting solution. Examples of suitable plasticisers include glycerol, sorbitol and fructose. Glycerol is particularly suitable, and is typically used at a concentration of 5wt%.

As an alternative to the doctor blade method of casting, the solution comprising the matrix polymer and the anaesthetic dissolved in a suitable solvent is simply poured into an open container, whereupon the solvent evaporates off. The resulting film is then provided with a support membrane, typically by adhesion.

The patches may be of any appropriate size or shape. Typically they may range in size from 1 to 5 cm2, preferably from 1 to 2 cm2. They may be circular, oval, square or rectangular. The thickness of the patch excluding the release liner is generally from 0.1 mm to 0.5 mm, for example from 0.157 mm to 0.464 mm. Taking the release liner into account the overall thickness is typically from 0.2 mm to 0.7 mm, for example from 0.227 to 0.627.

In a first embodiment of the invention, the patch is about 1.3 × 2.5 cm in area and comprises, as support membrane, a polyurethane-containing film (such as KM 1354-00 from Semex Medical) ; an anaesthetic-releasing film comprising about 25 mg lidocaine, about 25 mg of a poly(vinyl-pyrrolidone) polymer (such as PVP K-90 from Semex Medical) and about 25 mg of glycerol; and, as release liner, a silicone-treated paper of which a suitable example is 3402 from Semex Medical.

In a second embodiment, the patch differs from that of the first embodiment in that the anaesthetic releasing film comprises about 25 mg of lidocaine, about 32 mg of a PVP and about 14 mg of glycerol. This patch has less dry tack than the first.

In use, the patch is applied to the buccal mucosal or gingival region in need of anaesthetising. The patch adheres via the exposed surface of the polymer matrix film loaded with anaesthetic. Typically, the patch is positioned to cover the cervical margin of the tooth and its attached mucosa. It is therefore usually located away from the gingival margins.

The following Examples illustrate the invention. In the accompanying drawings:

Figure 1 shows the average cumulative fraction of lidocaine. HCl released from various films in the in vitro evaluation in Example 1;

Figure 2 shows the average cumulative fraction of lidocaine from various films in the in vitro evaluation in Example 2;

Figure 3 shows the average cumulative fraction of lidocaine released from PVP K-60 film in Example 2 which was sealed in polyurethane film or not;

Figure 4 shows the effect of a lidocaine.HCL-containing film on the electrical stimulation threshold of teeth in Example 3;

Figure 5 shows the in vitro release characteristics of lidocaine patches tested in Example 5, wherein the line marked ■ denotes the use of a buffer at pH 7.3 as receiving fluid and the line marked ▴ denotes pure water as the receiving fluid; Figure 6 shows the in vitro release characteristics of lidocaine patches tested in Example 6, and neat lidocaine tested in the Comparative Example, wherein the line marked ● denotes neat lidocaine, the line marked ■ denotes a patch containing 5.5 mg lidocaine and ▴ denotes a patch containing 12.6 mg lidocaine;

Figure 7 shows the in vitro release characteristics of lidocaine patches tested in Example 7, wherein the line marked ● denotes a patch incorporating sorbitol as a plasticiser and ■ denotes a patch without plasticiser;

Figure 8 illustrates the in vitro release characteristics of patches wherein the lidocaine film has two different thicknesses: the line marked ● denotes a thickness of 0.030 cm and ■ denotes 0.044 cm; and

Figure 9 illustrates the in vitro release characteristics of patches of different surface area, wherein the line marked ● denotes a patch of 3.25 cm2 and ■ denotes one of 1.00 cm2.

Example 1: Preparation and in vitro evaluation of lidocaine.HCl-loaded films

Films containing lidocaine.HCl were prepared from sodium carboxymethyl cellulose (CMC), Gantrez ES-225, polycaprolactone (PCL), PVP-40 and PVP K-60 by solvent casting in an open container at 50° C or at room temperature. Film preparation consisted of dissolving 25% lidocaine.HC1 and 75% of the polymeric excipient in either water, ethanol or acetic acid. The solution was poured into an open container that was lined with either Mylar (trade mark) or Teflon (trade mark). The solvent was evaporated at 50°C or at room temperature. Films prepared with PVP, PCL and Gantrez were soft and flexible, while those prepared from CMC were harder and more rigid. Dry or wet tack was determined by pressing either a dry or a moist finger onto the surface of the film and then observing the adhesion of the film to the finger. The results from the various films are summarised in Table 1.

TABLE 1 : LIDOCAINE .HCL-LOADEDa FILMS

Sample Film-forming Film Dry Wet

No. polymer thickness,b tack tack

E088 mm

-37-1 Gantrez ES-225 0.781 No Yes

-38-1 CMC 0.299 No Yes

-39-1 PVP K-60 0.813 Yes Yes

-40-1 PVP-40 NDc No Yes

-42-1 PCL ND No No

All films contained 25 wt% lidocaine.HCl. Film thickness was determined with a micrometer ND = not determined.

In vitro release experiments were carried out in triplicate using 1 cm2 samples of each film. Release from the films was allowed from only one surface by applying a poly(methyl methacrylate) (PMMA) backing to one side of the sample. The in vitro release of lidocaine.HCl was then determined by immersing the samples in separate containers of Sorensen's phosphate buffer. The sealed containers were incubated at 37°C and agitated at low speed in a shaker bath. Samples for analysis of lidocaine were removed at 5, 10, 20, 30 and 60 minutes. The quantity of lidocaine.HCl released was determined in these samples spectrophotometrically. Figure 1 shows the average cumulative fraction of lidocaine .HCl released from various films. Example 2: Preparation and in vitro evaluation of lidocaine-loaded films

Films containing lidocaine were prepared from PCL, PVP-40, PVP K-60, PVP K-90, Gantrez ES-225 and Rhoplex N-560 by solvent casting with a high-speed centrifugal spin caster. The preparation of blends for film formation was the same as that described for lidocaine.HCl. The lidocaine/polymer solution was injected with syringe into a spin-casting cup that was 8.9 cm (3.5 in.) in diameter, 7.6 cm (3.0 in.) deep and Mylar- or Teflon-lined. The cup was rotated at 3600 rpm until the solvent had evaporated. Then, the cylindrical film was removed from the cup and cut transversely to give a uniform, rectangular film. A film of CMC and 25% of lidocaine film was also prepared by dissolving the lidocaine and CMC in an ethanol/water mixture and solvent casting as described in Example 1. The results from the various films are summarised in Table 2.

TABLE 2 : LIDOCAINE-LOADEDa FILMS

Sample Film-forming Film Dry Wet

No. polymer thickness,b tack tack

E088 mm

-18-1 PCL 0.678 No No

-19-1 PVP-40 0.518 No Yes

-20-1 CMC NDc No Yes

-48-1 PVP K-60 0.627 No Yes

-52-1 PVP K-90 0.510 No Yes

-76-1 Gantrez ES -225 0.497 No Yes

-82-1 Rhoplex N- 560 ND Yes No

All films contained 25 wt % lidocaine.

Film thickness was determined with a micrometer c ND = not determined.

In vitro release experiments were carried on 1 cm2 samples of each film except CMC and Rhoplex N-560 in the same way as in Example 1. To limit the release of lidocaine to one surface of the sample, the sample was secured to a PMMA backing or to a polyurethane film via a medical grade adhesive. Figure 2 shows the average cumulative fraction of lidocaine released from the films.

In order to make a useful anaesthetic device, it was essential to have an impermeable backing material for the drug-loaded film. An experiment was carried out in which the PVP K-60 film containing lidocaine was completely sealed in polyurethane film. Unsealed and sealed material was then subjected to in vitro release studies as described previously. The results are presented in Figure 3. These show that only negligible amounts of lidocaine were able to penetrate the polyurethane film.

Example 3: In vivo evaluation of lidocaine .HCl-loaded PVP K-60 films

The clinical benefits of these films were evaluated in a study involving 9 human volunteers. In each subject a lidocaine-containing film and a placebo film were placed on contralateral sites on the gingiva. The films remained in place for 30 minutes. Anaesthesia of the mucosa was evaluated using a sharp probe. Conduction anaesthesia of the teeth was evaluated by measuring the electrical stimulation threshold of an appropriate tooth. Data describing the onset and duration of the soft tissue anaesthesia are presented in Table 3. The effect of the lidocaine-containing film on the electrical stimulation threshold of the teeth is presented in the accompanying Figure 4. TABLE 3 : Changes in soft tissue sensation.

Sensory change Time mins S.D. mins

Mucosa analgesic 7.4 3.4

Onset of lip paraesthesia

11.0 3.7

Return of normal sensation after patch removed

Mucosa 26.4 8.9

Lip 22.6 5.2

It is clear from these data that the lidocaine-containing films with a polyurethane backing produce anaesthesia of the mucosa which is of considerable depth and rapid onset. Furthermore, this anaesthesia remains localized to the area of application, and the strong unpleasant taste of the drug is not observed. The observed changes in conduction threshold indicate that application of lidocaine films designed in this manner can produce varying degrees of conduction anaesthesia of the teeth.

Example 4: Preparation of lidocaine loaded film by doctor blade method of casting

Films comprising lidocaine as the anaesthetic were prepared from PVP K-90 and a combination of PVP K-90 and PVP K-29/32. Ethanol was used as the casting solvent and the casting substrate was either the release liner, or a support membrane comprising one or two layers of KM 1345-00, an acrylic adhesive/polyester polyurethane from Semex Medical. The film was cast using a doctor blade in a fabrication box approx 76 cm × 35.5 cm × 15 cm (30" × 14" × 6") having a built-in manifold of five individually adjustable values to enable the flow rate and dispersion of nitrogen to be regulated. The composition of the casting solutions and the process conditions used are shown in Table 4.

TABLE 4

PREPARATION OF LIDOCAINE LOADED FILM BY DOCTOR BLADE METHOD OF CASTING

Process condition:

Composition of casting solutiona Catting Blade ht,

Sample wt % lidocaint/PVPb /plasticiterc substrate mil

E088-132-03 25/75/0 Support membrant (1)g E088-133-01 25/75/0 Support foamh 130

E088-133-02 25/75/0 Support foam 90

E088-139-01 25/75/0 Support membrane (1) 75/75J

E088-140-01 10/90/0 Support membrane (1) 75/75 E088-142-01 25/74.5/0.5k Support membrane (1) 75 E088-142-02 25/74.5/0.5k Support membrane (1) 75

F092-011-01 25/70/5 Support membrane (2) 75 F092-013-01 25/75/0 Support membrane (2) 75/100 F092-020-01 25/72/3 Support membrane (2) 50/100

F092-022-01 25/74/1k Support membrane (2) 50/100 F092-024-01 25/75/0 Support membrane (2) 50/100 F092-02S-01 25/75/0 Releate liner 100

F092-027-01 25/72/3 Support membrane (1) 75 F092-029-01 25/70/5 Support membrane (2) 75 F092-030-01 25/74/1k Support membrane (2) 75

F092-043-01 25/(50:25) /0 Releate liner 100 F092-044-01 2S/ (45:25) /5 Release liner 100 P092-045-01 50/50/0 Release liner 100

F092-O46-01 50/45/5 Releatt liner 100 F092-047-01 25/(50:25)/0 Releate liner 100 F092-348-01 25/(45:25)/5 Releatt liner 100

F092-049-01 50/50/0 Rtlease lintr 100 F092-050-01 50/45/5 Releate liner 100 F092-053-01 25/75/0 Releate liner 84

F092-056-01 50/45/S Releate liner 51 F092-056-02 50/45/5 Releate liner 51 F092-057-01 50/4S/5 Releate liner 31

F092-058-01 50/45/5 Releate liner 51 F092-059-01 50/45/5 Releate liner 51 F092-060-01 50/45/5 Releate liner 84

F092-065-01 25/(45:25) /5m Releate liner 84 TABLE 4 ( continued )

LidocaineFatch

N2 flow rate, Drying releasing film loading,f mg

Sample SCFHd time, he thickness, mm of lidocaine

E088-132-03 20 2 0.30 29

E088-133-01 20 2 NDi ND E088-133-02 20 2 0.18 16

E088-139-01 20 3 0.44 41 E088-140-01 20 3 0.48 18 E088-142-01 20 2 0.28 23 E088-142-02 20 2 0.23 13

F092-011-01 20 2 ND ND F092-013-01 20 4 0.39 39 F092-020-01 20 4 0.40 34

F092-022-01 20 4 0.31 21 F092-024-01 20 4 0.51 55 F092-025-01 20 2 0.41 36

F092-027-01 20 1 0.45 42 F092-029-01 20 1 0.28 27 F092-030-01 20 1 0.37 41

F092-043-01 4/10 6 0.45 78 P092-044-01 4/10 6 0.39 27 F092-045-01 4/10 6 0.39 77

F092-046-01 4/10 6 0.33 52 F092-047-01 16 2 0.39 38 F092-348-01 10 2 0.47 37

F092-049-01 10 2 0.53 78 F092-050-01 10 2 0.52 80 F092-053-01 10 2 0.29 25

F092-056-01 10 1 0.12 20 F092-056-02 10 1 0.18 35 P092-057-01 10 1 0.13 26

F092-058-01 10 3 0.13 20 F092-059-01 10 3 0.14 20 F092-060-01 10 2 0.40 50

F092-065-01 10 2 0.44 ND Footnotes to Table 4

a Casting solutions contained 30 wt % solids (lidocaine, PVP, plasticizer) and 70 wt % ethanol, unless otherwise noted, b PVP = PVP K-90 or a blend of PVA K-90 and PVP K-29/32

(w/w). c Plasticizer = Glycerol, unless otherwise noted, d SCFH = Standard cubic feet per hour, e Rounded off to nearest hour, f Lidocaine loading in a 3.25 cm2 patch (1.3 × 2.5 cm). The lidocaine loading was calculated using the weight of the patch and the initial lidocaine concentration in the casting solution. (It was assumed that the patch did not contain residual ethanol.) g Trade Name = KM1352-00 (Semex Medical, Frazer, PA), a polyurethane film coated with an acrylic adhesive.

Number in parenthesis indicates number of layers, h Trade Name = KM1952-00 (Semex Medical, Frazer, PA), a polyurethane foam coated with an acrylic adhesive, i ND = Not determined, j --/-- indicates two film layers were cast. The first layer was allowed to dry (about 1/2 the drying time), and then the second layer was cast on top of the first. k Plasticizer = sorbitol. l Casting solution contained 40 wt % solids and 60 wt % ethanol. m Casting solvent was water, solids/water, 30:70 (w/w). Example 5 In vitro evaluation of lidocaine patches produced by doctor blade casting

Patches loaded with 8.9 mg of lidocaine were suspended in purified water, at 37°C under infinite sink conditions, in an individual wire mesh cage to ensure that the lidocaine-loaded film was exposed at all times to the receiving fluid. Each sample was placed in an Eberbach shaker bath (Eherbach Corp; Ann Arbor, Ml) and agitated at 60 or 120 oscillations per minute (OPM). Periodically the caged patches were transferred to fresh water. Samples of the water exposed to the patches (the receiving fluid) were quantified for lidocaine by UV spectophotometry.

The above-described process was repeated using Sorensen's phosphate buffer (pH = 7.3) instead of water as the receiving fluid.

Figure 5 shows the release kinetics of the lidocaine patches tested as described above. They are seen to be very similar.

Example 6: Effect on in vitro release kinetics of the loading of the patch

Patches 1 cm2 in area were prepared by the method of Example 4, and were loaded with 12.6 mg or 5.5 mg of lidocaine (corresponding, respectively, to 25 wt% and 10 wt% of lidocaine in the film). Their in vitro release characteristics were evalluated by the process of Example 5, using deionised water at 37°C as the receiving fluid and an Eberbach shaker bath agitated at 60 oscillations per minute.

Figure 6 shows the dissolution profiles obtained. A change in the lidocaine loading appears to have little effect on the amount of lidocaine released from the patch.

Comparative Example: Release characteristic of neat lidocaine

Three samples of neat lidocaine, weighing 9.5 mg, 9.0 mg and 5.3 mg respectively were evaluated in vitro and dissolution profiles established. The results are shown in Figure 5, from which a comparison with the dissolution profiles obtained with two loaded patches indicates that the polymer matrix in the patches is exercising a control over lidocaine release.

Example 7: Effect on in vitro release characteristics of lidocaine from a patch of a plasticiser

To illustrate the effect of a plasticiser on lidocaine release from a patch, two patches were prepared by the method of Example 4, one including the plasticiser sorbitol in the polymer matrix:

Lidocaine Sorbitol per patch (mg) (mg) (wt%)

4.6 0.46 0.5

8.9 0.00 0.0

Figure 7 shows that sorbitol slightly increases lidocaine release. However, sorbitol is not ideal since its low solubility in the casting solution makes it impossible to incorporate more than 1% by weight in the patch. Glycerol has proved to be a preferably plasticiser since it may readily be incorporated in higher concentrations, typically 5% by weight.

Example 8: Effect of the lidocaine-releasing film thickness on in vitro release characteristics

Patches 1 cm2 in area were prepared by the method of Example 4.

Patch Lidocaine Film thicknesε (cm) per patch (mg)

1 8.9 0.030

2 12.6 0.044 They were tested by the process of Example 5 using deionised water at 37°C as receiving fluid and a shaker bath agitated at 60 oscillations per minute.

Figure 8 shows the dissolution profiles obtained, which indicate that a decrease in film thickness leads to an increase in lidocaine release. The difference in this particular instance appears to be only slight, although overall the thickness of the lidocaine film is observed to be one of the most important parameters in determining the total dose of lidocaine from a patch.

Example 9: Effect of surface area on release characteristics

Two patches of different surface area were prepared by the method of Example 4, as follows:

Patch Surface area Lidocaine loading

(cm2 ) (mg)

1 3.25 (1.3×2.5cm) 41.0

2 1.00 (1.00×1.00cm) 12.6

Their In vitro release characteristics were determined by the process of Example 5, using deionised water at 37°C as the receiving fluid and a shaker bath agitated at 60 oscillations per minute.

The results are shown in Figure 9, from which it is seen that an increase in surface area leads, as might be expected, to an increase in lidocaine release.

Claims

1. An anaesthetic patch suitable for use in the mouth, which comprises a biocompatible hydrophilic polymer matrix loaded with an anaesthetic, which matrix is capable of adhering directly to the oral mucosa without an adhesive, and an impermeable inert support membrane.
2. An anaesthetic patch according to claim 1 which includes a release liner positioned over the matrix loaded with anaesthetic.
3. An anaesthetic patch according to claim 1 wherein the impermeable inert support membrane is coterminous in area with the matrix loaded with anaesthetic.
4. An anaesthetic patch according to claim 1 wherein the polymer matrix includes one or more plasticisers.
5. An anaesthetic patch according to claim 4 wherein the polymer matrix includes glycerol or sorbitol.
6. An anaesthetic patch according to claim 1 wherein the polymer matrix comprises poly(vinylpyrrolidone) or a copolymer of methyl vinyl ether and maleic anhydride.
7. An anaesthetic patch according to claim 1 wherein the anaesthetic is lidocaine or lidocaine hydrochloride.
8. A method for producing an anaesthetic patch as claimed in claim 1 which comprises dissolving the anaesthetic and the hydrophilic polymer matrix in an inert solvent, spreading the resulting solution on a casting substrate by means of a blade and allowing the solvent to evaporate off.
9. A method according to claim 8 wherein the casting substrate is the release liner and wherein the support membrane is attached to the side of the loaded polymer matrix opposite to the release liner in a subsequent step.
10. A method of anaesthetising the buccal mucosa or the gingival region in a human or animal patient which comprises applying to the mucosae or region in need of anaesthetising an anaesthetic patch as claimed in any one of claims 1 to 8, or a patch produced by the method as claimed in claim 9.
PCT/GB1989/000491 1988-05-09 1989-05-09 Buccal local anaesthetic WO1989010740A1 (en)

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GB8810951.7 1988-05-09

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Application Number Title Priority Date Filing Date
PCT/GB1989/000491 WO1989010740A1 (en) 1988-05-09 1989-05-09 Buccal local anaesthetic

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GB (1) GB8810951D0 (en)
WO (1) WO1989010740A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015289A1 (en) * 1991-02-27 1992-09-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
EP0507160A1 (en) * 1991-03-30 1992-10-07 Teikoku Seiyaku Kabushiki Kaisha External preparation for application to the skin containing lidocaine
EP0537165A4 (en) * 1990-04-27 1993-02-24 Allergan Inc Polymeric drug delivery system.
US5332576A (en) * 1991-02-27 1994-07-26 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5719197A (en) * 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
WO1998017263A1 (en) * 1996-10-25 1998-04-30 Copley Pharmaceutical Inc. Transdermal patch
US7005142B2 (en) * 1999-06-25 2006-02-28 Thomas Leon Veterinary delivery systems and methods of delivering effective agents to animals
US9554976B2 (en) 2002-09-11 2017-01-31 The Procter & Gamble Company Tooth whitening product
US9956211B2 (en) 2011-04-29 2018-05-01 Moberg Pharma Ab Pharmaceutical compositions comprising a local anaesthetic such as bupivacaine for local administration to the mouth or throat
US10285915B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1108837A (en) * 1965-11-30 1968-04-03 Astra Pharma Prod Improvements in material for causing local anaesthesia
EP0200508A2 (en) * 1985-04-27 1986-11-05 Nitto Denko Corporation Adhesive oral bandages and oral pharmaceutical preparations
EP0250187A2 (en) * 1986-06-16 1987-12-23 JOHNSON & JOHNSON CONSUMER PRODUCTS, INC. Bioadhesive extruded film for intra-oral drug delivery and process

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1108837A (en) * 1965-11-30 1968-04-03 Astra Pharma Prod Improvements in material for causing local anaesthesia
EP0200508A2 (en) * 1985-04-27 1986-11-05 Nitto Denko Corporation Adhesive oral bandages and oral pharmaceutical preparations
EP0250187A2 (en) * 1986-06-16 1987-12-23 JOHNSON & JOHNSON CONSUMER PRODUCTS, INC. Bioadhesive extruded film for intra-oral drug delivery and process

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719197A (en) * 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
EP0537165A4 (en) * 1990-04-27 1993-02-24 Allergan Inc Polymeric drug delivery system.
EP0537165A1 (en) * 1990-04-27 1993-04-21 Allergan, Inc. Polymeric drug delivery system
US5474780A (en) * 1990-04-27 1995-12-12 Allergan, Inc. Monolithic maleic anhydride drug delivery systems
EP0728477A3 (en) * 1991-02-27 1996-09-11 Noven Pharma
US5234957A (en) * 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5332576A (en) * 1991-02-27 1994-07-26 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
EP0728477A2 (en) * 1991-02-27 1996-08-28 Noven Pharmaceuticals, Inc. Compositions for topical administration of pharmaceutically active agents
WO1992015289A1 (en) * 1991-02-27 1992-09-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
EP0507160A1 (en) * 1991-03-30 1992-10-07 Teikoku Seiyaku Kabushiki Kaisha External preparation for application to the skin containing lidocaine
US5827529A (en) * 1991-03-30 1998-10-27 Teikoku Seiyaku Kabushiki Kaisha External preparation for application to the skin containing lidocaine
WO1998017263A1 (en) * 1996-10-25 1998-04-30 Copley Pharmaceutical Inc. Transdermal patch
US7005142B2 (en) * 1999-06-25 2006-02-28 Thomas Leon Veterinary delivery systems and methods of delivering effective agents to animals
US9554976B2 (en) 2002-09-11 2017-01-31 The Procter & Gamble Company Tooth whitening product
US9956211B2 (en) 2011-04-29 2018-05-01 Moberg Pharma Ab Pharmaceutical compositions comprising a local anaesthetic such as bupivacaine for local administration to the mouth or throat
US10285915B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives
US10285916B2 (en) 2012-10-17 2019-05-14 The Procter & Gamble Company Strip for the delivery of an oral care active and methods for applying oral care actives

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