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WO2001037814A1 - Comprimes bicouches a administration buccale comprenant de la nicotine - Google Patents

Comprimes bicouches a administration buccale comprenant de la nicotine Download PDF

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Publication number
WO2001037814A1
WO2001037814A1 PCT/GB2000/004428 GB0004428W WO0137814A1 WO 2001037814 A1 WO2001037814 A1 WO 2001037814A1 GB 0004428 W GB0004428 W GB 0004428W WO 0137814 A1 WO0137814 A1 WO 0137814A1
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WO
WIPO (PCT)
Prior art keywords
tablet
release
substance
tablet according
nicotine
Prior art date
Application number
PCT/GB2000/004428
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English (en)
Other versions
WO2001037814A9 (fr
Inventor
Calum Park
Dale Munday
David Francis Bain
Omar Shakoor
Original Assignee
Robert Gordon University
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 claimed from GBGB9927525.7A external-priority patent/GB9927525D0/en
Priority claimed from GB0021645A external-priority patent/GB0021645D0/en
Application filed by Robert Gordon University filed Critical Robert Gordon University
Priority to AU17135/01A priority Critical patent/AU1713501A/en
Priority to EP00979743A priority patent/EP1231900A1/fr
Publication of WO2001037814A1 publication Critical patent/WO2001037814A1/fr
Publication of WO2001037814A9 publication Critical patent/WO2001037814A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • This invention relates to the delivery of substances such as bio-active agents and pharmaceuticals to the body.
  • the invention concerns the delivery of nicotine to the buccal area.
  • Nicotine replacement therapy is a frequent component of strategies to help smokers stop smoking.
  • Present NRT delivery systems include chewing gum and transdermal patches which release the drug over a period of time but do not provide an initial surge of rapidly released drug that mimics the effect of cigarette inhalation; nasal sprays and inhalers are also available which deal with this problem, but these methods do not permit long term release.
  • a method of delivering a substance to the buccal mucosa of a subject comprising providing a tablet comprising a quantity of the substance to be delivered, the tablet having multi-phasic release properties to release controlled amounts of the substance to the subject over time, and releasing the substance from the tablet in the subject's mouth.
  • the invention also provides a tablet for delivery of a substance to the buccal mucosa of a subject, the tablet comprising a quantity of substance to be delivered to the subject, the tablet having multi- phasic release properties adapted to release controlled amounts of the substance to the subject over time.
  • the tablet can be of conventional physical design but any vehicle capable of bearing the substance and dissolving in the mouth can be used.
  • the tablet may have a multi-layer structure with different amounts of substance associated with each layer. This can be by making different homogeneous layers with different release characteristics or by enclosing different quantities of substance within layers of e.g. coating that can dissolve at different rates, thereby deferring the time until the fluids in the mouth dissolve the substance and/or the tablet matrix.
  • the tablet may comprise a bioadhesive such as Carbopol (TM) or chitosan, or a similar bioadhesive polymer, and this can optionally be in a separate adhesive layer, or can be incorporated into another part of the tablet, such as the slow (or controlled) release layer.
  • TM Carbopol
  • the inventors have found that these compounds also assist in controlling the release of the substance.
  • the tablet may also contain other agents to control the release of the substance such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, poly D L lactide- and/or glycolide- related polymers.
  • Such polymers are very useful in the present invention as they swell when hydrating and this can be used to control the release characteristics of the substance which is retarded in the swollen polymer until the polymer starts to dissociate from the tablet. This can be used to change the release characteristics of the tablet without necessarily changing the amount of substance in the tablet, and without layering the tablet. Thus multi -phasic release properties can be achieved with a homogeneous tablet.
  • the outer layer of the tablet may be adapted to release a quantity of the substance very quickly to satisfy a craving in the subject for addictive substances.
  • the substance is nicotine.
  • Other substances are also suitable such as cannabinoids , antibiotics, analgesics or anaesthetics such as lidocaine for direct application to mouth ulcers etc or for use prior to or following dental treatment, and drugs for other buccal infections.
  • cannabinoids such as cannabinoids
  • antibiotics such as pirin, pirin, pirin, pirin, pirin, pirin, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofefen, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofitopril
  • the inner layer or layers may be associated with slower release of substance.
  • the layers may contain the substance as an integral component of the layers or the substance may be provided in a separate layer beneath coatings that exhibit the desired release characteristics.
  • the layers may be made up of a material that is adapted to dissolve at a known rate so as to release the substance underneath the layer or trapped within it at a set time after the tablet is placed in the mouth.
  • the outer layers are preferably capable of releasing substance at a different (preferably faster) rate than the inner layers.
  • the tablet formulation consists of two distinct layers, each of which has a specific function.
  • a controlled release layer containing a bioadhesive is attached to the mucosal tissue lining the cheek adjacent to the gum (gingiva) in the buccal area of the patient's mouth.
  • the rapid release layer Upon contact with saliva the rapid release layer disintegrates and releases nicotine, which is subsequently absorbed through the oral mucosa into the systemic circulation.
  • This immediate release and absorption of nicotine is designed to reduce or eliminate the cravings for nicotine of the smoker, particularly those following a meal (post-prandial cravings) .
  • the time period over which the tablet remains attached to the buccal mucosa typically determines the time period over which nicotine is released. This is potentially up to three or four hours.
  • nicotine is being absorbed into the systemic circulation at a constant rate (referred to as zero order release) , independent of the amount of nicotine remaining in the formulation, thus eliminating further cravings for nicotine.
  • the user may, at any time, detach and remove the tablet if they think this appropriate.
  • One possible scenario of usage is removal of the tablet prior to eating a meal followed by attachment of a new tablet following completion of the meal .
  • Typical dimensions of the tablet are 6mm diameter and 3mm thickness. These dimensions are usefully independent of nicotine or other substance content as any reductions in the same are compensated for by increased amounts of diluent to maintain tablet weight and dimension.
  • Carbopol C934 has been extensively studied and been shown to produce excellent adhesion to mucosal membranes.
  • the bioadhesive strength of this poly (acrylic) acid polymer increases with polymer concentration up to 25% w / w and thereafter remains relatively constant and a tablet containing 5-50 % C934 can adhere to the gingiva for 550-600 minutes.
  • C934 was therefore favoured as the mucoadhesive polymer in the formulation at a preferred concentration of around 20 % w / w where mucoadhesive strength is near maximum and below the 50 % concentration, which has the potential to cause some mucosal irritation.
  • HPC is effective in producing controlled drug release.
  • the layers of the tablet need not be concentric although in certain embodiments this is preferred. In certain embodiments shown in the examples following the tablet has two (or more) flat layers in a "sandwich" structure.
  • Fig. 1 is a schematic view of a tablet
  • Fig. 2 is a graph of representative nicotine release profiles from dosage forms
  • Fig. 3 is a diagrammatric representation of drug release from a poylmer matrix
  • Fig. 4 is a graph of release of nicotine from a bi-layer tablet
  • Fig. 5 is a schematic diagram of diffusion apparatus used in the methods described
  • Fig. 6 is a graph of water uptake profiles for buccal adhesive tablets
  • Fig. 7 is a graph of NHT dissolution profiles for buccal adhesive formulations
  • Fig. 8 is a graph of diffusional exponent values for nicotine buccal adhesive tablets
  • Fig. 1 is a schematic view of a tablet
  • Fig. 2 is a graph of representative nicotine release profiles from dosage forms
  • Fig. 3 is a diagrammatric representation of drug release from a poylmer matrix
  • Fig. 4 is a graph of release of nicotine from a bi-layer tablet
  • Fig. 5 is a schematic diagram of diffusion apparatus used in the methods described
  • FIG. 9 is a graph of NHT kinetic rate constant values for nicotine buccal adhesive tablets
  • Fig. 10 is a graph demonstrating the linear relationship between NHT release rates and HPC content of nicotine buccal adhesive tablets using diffusion dissolution apparatus
  • Figs. 11 and 12 are graphs showing dissolution profiles for bilayer tablets
  • Fig. 13 shows drug release profiles of NHT bilayer tablets over the first hour of a 4 hour flow through dissolution test.
  • Controlled release formulations A - F were produced as shown in Table 1.1, containing nicotine in the form of NHT, PVP to act as a binding agent, lactose as a diluent and magnesium stearate as a lubricant. C934 was included to impart adhesive properties and HPC was included in a range of concentrations to investigate its effect on NHT release.
  • PVP molecular weight 44000
  • Carbopol (TM) 934P is a synthetic high molecular weight cross-linked polymer, which imparts bioadhesive properties on the formulation. In addition this polymer also has release-controlling and binding properties.
  • Spray-dried lactose is included as an inert diluent.
  • the physical and chemical properties of this material are ideal for use as such an agent.
  • HPC is a semi-synthetic polymeric cellulose derivative which has matrix- forming properties. Once hydrated the drug can diffuse out of the matrix. This material thus has drug release controlling properties.
  • Magnesium stearate was optionally added as a glidant and anti-adherent agent which facilitates powder flow (essential for successful tablet production) and prevents adherence of the powder materials to the tooling of the tablet manufacturing apparatus.
  • Table 1 . 1 Excipient concentrations used in the preparation of formulations A - F .
  • MGS 1 1 1 1 1 1 1 1 NHT nicotine hydrogen tartrate
  • PVP polyvinylpyrolidone
  • C934 carbopol
  • HPC hydroxypropylcellulose
  • SDL spray dried lactose
  • the excipients were weighed accurately and physically mixed by shaking in a bag for 10 minutes. Powder mixes were used to produce 100 mg tablets by direct compression using an eccentric tablet press (model F3 , Manesty machines Ltd, Liverpool, UK) using 6 mm punches.
  • the dose of nicotine may be varied depending on requirements and a corresponding reduction in mannitol amount maintains tablet dimensions constant .
  • the RRL is optionally formed by mixing the above ingredients and compressing them in a mould of desired shape to form the layer.
  • Bilayer nicotine buccal tablets were formulated. Burst release of NHT from a rapid release layer to satisfy a craving for nicotine, followed by prolonged release of nicotine from a controlled release layer to prevent reoccurrence of the nicotine cravings. Rapid release layers (RRL) were formulated using the excipients listed in table 1.2
  • Bilayer tablets were produced using a 2-stage compression cycle.
  • the controlled release layer (CRL) was first formed by direct compression of powder mixes A - F in table 1.1. The CRL was left in the tablet die and the bottom punch lowered. 50 mg of the RRL was added to the die and the second compression carried out.
  • the bilayer tablets were 6 mm x 4.5 mm in dimension and are depicted in figure 1.
  • Bilayer tablets containing both 2 mg and 5 mg RRL were prepared with each CRL (A - F) .
  • the RRL could be distinguished from the CRL layer by the pure white colour of the RRL through the use of mannitol.
  • the addition of a pharmaceutical pigment would allow the user to distinguish the layers and identify which layer should be attached to the gingiva (gum) .
  • Example 2 In this example the RRL was as described in example 1 above, and the CRL was as follows:
  • the two layers of the overall tablet were separately fabricated; although combined fabrication of whole tablets is generally within the scope of a skilled man.
  • the RRL ingredients were mixed and granulated using ethanol as the granulating fluid, followed by compression into tablets; for the CRL the ingredients were dry mixed and tablets formed by direct compression. The two individual tablet layers were then replaced in the die of a tablet press and compressed for a second time, resulting in the formation of one coherent bilayer tablet.
  • the tablet manufacturing apparatus employed for the fabrication was a standard single punch eccentric press with no modifications.
  • a specialised double compression tablet press can be used for the rapid production of larger batches of product.
  • the drug release profiles demonstrate the biphasic nature of the release from the bilayer formulations: an initial burst release of nicotine followed by retarded zero order drug release. This characteristic is absent from the single layer controlled release tablets, which release drug in a monophasic zero order kinetic manner. The initial burst nicotine release is essentially complete within 30 minutes. This result contradicts the disintegration time of the RRL of 4 minutes. However, differences in the hydrodynamic properties of the two test methodologies account for such contradictory results; nonetheless, it is believed that the faster release initially would sufficiently satisfy initial craving rapidly, and encourage buccal absorption, rather than the swallowing of saliva and consequent unpleasant gastro-intestinal effects.
  • the mechanism by which drug release is retarded in the controlled release formulations is thought to be due to the formation of a matrix of drug and polymer (s) during fabrication and subsequent contact with the dissolution medium.
  • the drug is evenly dispersed within this matrix, as shown in Fig 3.
  • the dissolution medium can enter through pores in the matrix, dissolve the drug and the resulting drug solution diffuses out of the matrix.
  • This type of mechanism normally results in first order drug release, as diffusion is a first order process, i.e. the rate of diffusion is dependent on the amount of drug remaining in the formulation.
  • the observation of zero order drug release from the formulations produced is thought to be due to a complex combination of drug diffusion, matrix erosion and interaction of oppositely charged nicotine (cationic) with anionic substituent groups on the Carbopol (TM) molecule, i.e. the -COOH groups.
  • Table 3 . 1 shows the formulation ingredient quantities of the controlled release layer of further embodiments A- I .
  • the rapid release layer contained 2 mg NIC, 4 mg PVP 10000 and 44 mg mannitol.
  • the two layers were produced individually by direct compression (8mm punch) .
  • Bilayer tablets were produced by manually compressing the two layers together (Manesty F3 , Liverpool, UK) .
  • PVP polyvinylpyrrolidone
  • HPC hydroxpropylcellulose*
  • MgS magnesium stearate
  • Equation 1 an exponential expression used to analyse controlled release behaviour of pharmaceutical systems, was employed to investigate the dissolution data (Peppas and Sahlin, 1989 Int. J. Pharmaceutics 57:169-172) .
  • M t / M ⁇ is the fraction of drug released
  • k is the kinetic constant
  • n is the diffusion exponent for drug release.
  • This equation can be applied to the first 60 % of drug release to identify the type of drug release from the system.
  • a plot of log (M c / M ⁇ ) versus log t gives a straight line of gradient n and intercept log k.
  • Fig. 4 shows release profiles from tablets (US paddle) and demonstrates the efficient release from the rapid release layer of sample I (98% of the nicotine was released after 10 minutes) .
  • Example 4 Dosage forms formulated as above were tested to ensure that the patient receives a product containing the required amount of drug substance in a form that enables the drug substance to exert its full pharmacological action.
  • the standard tests included uniformity of weight, uniformity of content, disintegration (where appropriate) and dissolution, and the non-standard crushing strength and resistance to abrasion tests.
  • the crushing strength test involves application of a compressive load to the tablet to induce breaking. Sophisticated testers apply the force at a constant rate to improve reproducibility over simple hand operated devices. However, even when the load is applied at a constant rate, the variation in strength within a batch may be considerable.
  • a tablet during a normal life, will be exposed to forces in production, packaging or transportation procedures. These forces whilst not severe enough to break the tablet, may abrade small particles from its surface.
  • a friability tester is used, which subjects tablets to a uniform tumbling action, for a specified time, and the weight loss from the tablets is measured.
  • a swellable matrix is used to control the release of drug, and polymer swelling is an important stage in the formation of a mucoadhesive bond between such formulations and the mucosa. In vi tro swelling studies were therefore carried out.
  • Vi tro NHT dissolution was analysed using two different methods.
  • the first involved flow through dissolution apparatus, where the buccal adhesive tablets were exposed to 20 mL dissolution medium.
  • the second method is a novel method, devised to more accurately represent the in vivo conditions to which a buccal adhesive tablet might be exposed.
  • the method used a transdermal tester and following NHT dissolution from the tablet in a small volume ( ⁇ 0.5 mL) the detected NHT diffuses across a membrane in to a 5 mL cell.
  • the tablets were placed separately in a 20 mL cell in the flow through dissolution tester.
  • the dissolution medium was distilled water supplied at a flow rate of 100 mLhr "1 by a pump (model 202u, Watson - Marlow, Falmouth, U.K.) and at 37°C from an electric water heater (model W14, Grant Instruments, Cambridge, U.K.) .
  • the effluent from the cells was collected over a 4 hour period and assayed at certain time intervals using U.V. detection at 259 nm (model UV 300, Unicam LTD, Cambridge, U.K.) .
  • a transdermal tester as shown in Fig . 5 (model HDT 10 , Copley Scientif ic Ltd . , Nott ingham, U . K . ) was used for testing diffusion of the substance across a cell membrane.
  • Tablets from each batch were weighed and the theoretical nicotine contents were calculated and noted.
  • the experimental membrane was secured tightly to the cells, as show above. Single layer visking dialysis membrane or porcine buccal mucosa was used as the test membrane. Buccal mucosa was collected and prepared. Porcine mucosa was used the same day as the animal was sacrificed. The 5 mL cells were then filled with distilled water from the solution reservoir and the clamps secured. The cell stirrers and the cell heater were switched on to heat the solution to 37°C. To start, 100 ⁇ L of water was placed on the upper side of the membrane and the tablet was placed gently on the surface.
  • the NHT recovered during the assay is quoted as a percentage of the theoretical NHT in the tablet (10 % of tablet weight) .
  • the mean percentage NHT recovered for each tablet batch is tabulated below in table 4.2.
  • the mean tablet crushing strengths are shown below in table 4.3.
  • Formulations A - D do not show marked differences in crushing strength and combined with the relatively large standard deviations firm conclusions may not be drawn.
  • Formulations E and F with 40 % and 50 % HPC show slightly higher crushing strengths than the other formula ions, perhaps due to the ability of HPC to act as a binding agent.
  • buccal release tablets There are no recommendations for buccal release tablets and as the tablets are designed to swell as opposed to disintegrate and dissolve as with an oral tablet, the higher values noted are perhaps appropriate.
  • the percentage weight loss of five tablets from each batch after 5 minutes friability testing is tabulated in table 4.4.
  • the friability tests are designed to simulate conditions that may be experienced by a tablet during production, packaging and transportation.
  • the weight loss from the tablets has been demonstrated to be extremely low perhaps as a function of the tablet hardness.
  • the swelling profile formulation A is considerably greater than observed for formulations B - F. Over the first 6 hours, formulation A has a more rapid weight increase due to a greater uptake of water. The formulation then continues to take up water over the 24 hour test period resulting in a 175.5 % ( ⁇ 2.55 % RSD) weight increase compared with the dry tablet weight. This larger and more rapid weight increase is due to the absence of HPC from the formulation, which allows the hydrophilic polymer carbopol to uptake the water in to the buccal tablet.
  • Figure 6 also indicates that there is little or no difference between the swelling profiles of formulations B - F, which contain between 10 and 50 % HPC. These formulations do not swell to a great extent after the first 6 hours.
  • Formulation B gains an average of 13.5 % in weight between 6 and 24 hours, formulations C - F gain between 1.39 and 4.27 %, which suggests that the formulations are approaching maximal swelling at approximately 6 hours.
  • the addition of HPC to the formulation appears to counteract the strong swelling properties of carbopol, this may be explained by the hydrated matrix properties of HPC which controls the penetration of water into the tablet. Concentrations of 20 - 50 % HPC show no significant difference in weight gain (swelling rate) between 6 - 24 hours.
  • the tablet dimensions measured over the 24 hour period showed similar trends compared to the weight increase.
  • large experimental standard deviations 2.5 - 33 % RSD
  • an increase in the HPC concentration of the formulation resulted in a smaller size increase of the tablet.
  • the dimensions of formulation A increased to a larger extent than formulations B - F, which swelled to a comparable extent. This may again be explained by the matrix forming properties of HPC, which controls the uptake of water by the formulation.
  • the tablet size increase for formulations B - F between 6 and 24 hours is again very small, again suggesting that at 6 hours the tablets are approaching maximal swelling.
  • the actual data is recorded in tables 4.5. and 4.6.
  • HPC a semi -synthetic polymeric derivative of cellulose
  • HPC gel acts as a physical barrier through which the dissolution medium must penetrate to dissolve the drug, the drug solution must then again penetrate the gel to be available for absorption.
  • Carbopol on the other hand is hydrophilic and will swell faster and to a greater extent, promoting the penetration of the dissolution medium into the tablet matrix. The alteration of polymer content of the matrix will alter the drug release rate.
  • Formulation A containing no HPC should allow the dissolution medium to penetrate the tablet, dissolve the drug and diffuse out of the tablet, resulting in rapid drug release.
  • Formulations B - F containing increasing HPC content should retard drug release by forming the gel barrier resulting in controlled drug release over a number of hours. Due to the small differences in swelling of formulations B - F, it is not possible to predict any differences with regard to drug dissolution.
  • Nicotine release profiles for formulations A - F are shown in figure 7. From figure 7 it can be seen that only approximately 50 - 60 % drug release was achieved form the formulations. HPC was expected to control the release in such a manner over the 4 hour period, it is therefore surprising that formulation A containing no HPC released only 60 % of NHT in this time.
  • n value allows the release mechanism from a cylindrical system such as a tablet to be characterised according to table 4.7. (Peppas and Sahlin 1989) .
  • Fickian diffusion describes t "2 kinetics and case II transport describes constant zero order drug release. Polymer swelling and drug diffusion through a matrix do not normally follow Fickian release behaviour, due to the existence of a molecular relaxation process (Vigoreaux and Ghaly 1994 Drug Development and Industrial Pharmacy 20(16) 2519-2526). This type of drug release results in intermediate values for n and is classed as anomalous (non Fickian) transport.
  • n value for formulation A is almost exactly mid range for anomalous non-Fickian release mechanism.
  • the n value increases in the other formulations that contain HPC.
  • Formulations C and D containing 20 and 30 % HPC respectively show n values approaching case II transport i.e. zero order NHT release.
  • the n values appear to tail off. This suggests the most appropriate matrix for NHT release contains around 20 - 30 % HPC providing release approaching zero order.
  • the variation of the diffusional exponent (n) with HPC is summarised in figure 8.
  • the kinetic rate constants (k) in table 4.8 incorporate the structural and geometrical characteristics of the release device and may be used to compare formulations.
  • Formulation A containing no HPC exhibits the greatest rate constant (k) .
  • the addition of HPC, as a matrix former results in a decrease in the rate constant as the hydrated HPC provides a barrier to drug dissolution. The rate decreases to a minimum at 30 % and remains relatively constant with increasing HPC concentration.
  • the variation in kinetic rate constant with HPC content is shown graphically in figure 9.
  • the dissolution statistics are presented in table 4.9.
  • the diffusion dissolution apparatus was set up using porcine buccal membrane. Due to the limited supply of porcine mucosa, this experiment was carried out once with formulation A. Using HPLC detection,' only 1.4 % of the NHT content of the tablet was recovered in the receptor solution after 4 hours. This figure is very low compared with the artificial membrane and may be due to the thickness of the membrane and problems of using animal tissue. The experiment was repeated using formulation A and fresh porcine mucosa, however instead of sampling from the receptor solution, after 4 hours that tablet was assayed to determine the NHT remaining in the formulation. Following this method, the HPLC tablet assay detected 6.95 mg of NHT remaining, which was calculated to be 69 % of the NHT content of the tablet.
  • NHT 31 % of the available NHT (3.11 mg) had been released from the tablet. All the NHT release was not able to cross the porcine membrane and enter the receptor solution, most likely due to the 2 mm thickness of the membrane (the upper 200 ⁇ m is known to be the barrier to buccal permeation) and the small orifice (0.785 cm 2 ) available for the NHT to enter the receptor solution. From this data it is suggested that the NHT has been released from the formulation and partitioned into the buccal tissue; however due to the reasons mentioned above, the NHT remained in the tissue and was not passed into the receptor solution.
  • formulation CRL B + RRL 2 mg formulation CRL D + RRL 5 mg .
  • the NHT recovered during the assay is quoted as a percentage of the theoretical NHT in the tablet.
  • Formulation CRL B + RRL 2 mg was again used for the friability determination using the method outline for formulations A - F.
  • 5 tablets lost 0.15 % of their combined weight. This is higher that the 0.06 % for formulation B controlled release monolayers alone, however this value is still low. The two layers remained joined and intact after the 5 minute test . This suggests that the bilayer tablets would be resistant to abrasion and therefore resistant to loss of tablet weight, including the loss of active ingredient, through normal processes until the product is used.
  • NHT release from the bilayer tablets was analysed using the flow through dissolution method outlined above .
  • Release profiles for bilayer tablets containing controlled release layers A and E are shown in figures 11 and 12. These profiles are representative of the trends seen in the release behaviour of all bilayer tablets.
  • Figures 11 and 12 show that the bilayer tablets produce a biphasic drug release profile, with a more rapid release of nicotine over the first hour of dissolution testing. Additionally, the rate of drug release from the bilayer tablet with the 5 mg RRL was greater than that from the bilayer tablet containing the 2 mg RRL. This trend was seen in all bilayer tablet batches produced.
  • Figure 4.10 indicates that the NHT release from bilayer tablets over the first hour followed zero order release kinetics.
  • the time taken for the bilayer tablet to release the 2 mg NHT was 27.78 minutes (8.44 % RSD). This compares favourably to the 26.35 minutes identified above. Due to the agreement in results, the one hour dissolution experiment was not repeated with the 5 mg RRL.
  • n values are all within the range indicating anomalous non-Fickian release mechanism.
  • table 4.11. indicates that the n values for the bilayer tablets containing 5 mg RRL are lower than for the bilayer tablet containing the 2 mg RRL and both are lower that the CRL monolayers alone.
  • the addition of the 5 mg RRL results in this value decreasing and the mechanism of release, although still anomalous transport, now approaches Fickian type release where drug release occurs by diffusion of the drug due to a chemical potential gradient .
  • the departure from zero order release may be explained by the distinct biphasic release profiles identified above, where rapid release from the RRL occurs over the first hour, followed by NHT release approaching zero order kinetics over the remaining 3 hours.
  • the tablet can include a sugar such as mannitol, sucrose or glucose that can contain the substance to be released within the tablet and can also improve the taste of the tablet in the mouth. Any sugar can be suitable for this purpose .

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Abstract

La présente invention concerne un procédé servant à administrer une substance telle qu'un médicament, à un sujet, ledit procédé comprenant l'application d'un comprimé ou d'une autre forme posologique sur une muqueuse buccale, la forme posologique étant conçue pour permettre une libération en plusieurs phases, comprenant en général une libération initiale en masse de la substance, suivie d'une libération contrôlée pendant une durée supérieure. La substance est en général de la nicotine.
PCT/GB2000/004428 1999-11-23 2000-11-22 Comprimes bicouches a administration buccale comprenant de la nicotine WO2001037814A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU17135/01A AU1713501A (en) 1999-11-23 2000-11-22 Bilayered buccal tablets comprising nicotine
EP00979743A EP1231900A1 (fr) 1999-11-23 2000-11-22 Comprimes bicouches a administration buccale comprenant de la nicotine

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EP1260216A1 (fr) * 2001-05-15 2002-11-27 Peirce Management, LLC Composition pharmaceutique multicouche destinee a une administration a la fois orale et intraorale
US6863901B2 (en) 2001-11-30 2005-03-08 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
EP1937414A2 (fr) * 2005-09-19 2008-07-02 University Of The Witwatersrand Johannesburg Forme pharmaceutique pour muqueuses orales
EP1980245A1 (fr) * 2007-04-11 2008-10-15 Cephalon France Composition pharmaceutique bicouche lyophilisée et ses procédés de fabrication et d'utilisation
US7585520B2 (en) 2001-12-05 2009-09-08 Collegium Pharmaceutical, Inc. Compositions containing both sedative and non-sedative antihistamines and sleep aids
WO2010044736A1 (fr) * 2008-10-14 2010-04-22 Mcneil Ab Forme posologique intra-orale à parties multiples et son utilisation
EP2233134A1 (fr) 2009-03-27 2010-09-29 McNeil AB Dosage intra-buccal multi-portions avec des propriétés organoleptiques
EP2432437A2 (fr) * 2009-05-21 2012-03-28 Bionex Pharmaceuticals LLC Formes pharmaceutiques bicouches et monocouches
US20120219628A1 (en) * 2009-10-30 2012-08-30 Ix Biopharma Pte Ltd Fast dissolving solid dosage form
US8343532B2 (en) 2003-09-05 2013-01-01 Arrow No. 7 Limited Buccal drug delivery
FR2993778A1 (fr) * 2012-07-30 2014-01-31 Pf Medicament Pastilles a cinetiques multiples de liberation de principes actifs
US9629832B2 (en) 2002-12-20 2017-04-25 Niconovum Usa, Inc. Physically and chemically stable nicotine-containing particulate material
US10098376B2 (en) 2003-11-07 2018-10-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10213586B2 (en) 2015-01-28 2019-02-26 Chrono Therapeutics Inc. Drug delivery methods and systems
US10219999B2 (en) 2006-03-16 2019-03-05 Niconovum Usa, Inc. Snuff composition
US10258778B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US10653686B2 (en) 2011-07-06 2020-05-19 Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US10716764B2 (en) 2003-10-27 2020-07-21 Morningside Venture Investments Limited Transdermal drug delivery method and system
CN111989002A (zh) * 2018-03-09 2020-11-24 株式会社Cl制药 无烟香烟用组合物及包含其的口腔溶解膜型无烟香烟
CN112220756A (zh) * 2020-10-16 2021-01-15 重庆市义力医药科技有限公司 一种尼古丁颗粒组合物及其制备方法
CN112444466A (zh) * 2019-09-05 2021-03-05 上海新型烟草制品研究院有限公司 一种用于评价口含烟烟碱体外吸收的方法
US10945454B2 (en) 2003-11-07 2021-03-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US20220347095A1 (en) * 2009-10-30 2022-11-03 Ix Biopharma Ltd Solid Dosage Form
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems

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AU2002252685C1 (en) * 2001-04-20 2002-11-05 Lavipharm Laboratories Inc. Intraoral delivery of nicotine for smoking cessation
EP1389910A1 (fr) * 2001-04-20 2004-02-25 Lavipharm Laboratories, Inc. Distribution intrabucale de nicotine destinee a arreter de fumer
EP1389910A4 (fr) * 2001-04-20 2005-11-02 Lavipharm Lab Inc Distribution intrabucale de nicotine destinee a arreter de fumer
EP1260216A1 (fr) * 2001-05-15 2002-11-27 Peirce Management, LLC Composition pharmaceutique multicouche destinee a une administration a la fois orale et intraorale
US6863901B2 (en) 2001-11-30 2005-03-08 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US7387792B2 (en) 2001-11-30 2008-06-17 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US7585520B2 (en) 2001-12-05 2009-09-08 Collegium Pharmaceutical, Inc. Compositions containing both sedative and non-sedative antihistamines and sleep aids
US9629832B2 (en) 2002-12-20 2017-04-25 Niconovum Usa, Inc. Physically and chemically stable nicotine-containing particulate material
US8343532B2 (en) 2003-09-05 2013-01-01 Arrow No. 7 Limited Buccal drug delivery
US8603516B2 (en) 2003-09-05 2013-12-10 Gelmedic Holding Aps Buccal drug delivery
US8603517B2 (en) 2003-09-05 2013-12-10 Gelmedic Holdings APS Buccal drug delivery
US10716764B2 (en) 2003-10-27 2020-07-21 Morningside Venture Investments Limited Transdermal drug delivery method and system
US10945454B2 (en) 2003-11-07 2021-03-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10765140B2 (en) 2003-11-07 2020-09-08 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10098376B2 (en) 2003-11-07 2018-10-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10258778B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US11471424B2 (en) 2004-09-13 2022-10-18 Morningside Venture Investments Limited Biosynchronous transdermal drug delivery
US10258738B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, AIDs, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
EP1937414A2 (fr) * 2005-09-19 2008-07-02 University Of The Witwatersrand Johannesburg Forme pharmaceutique pour muqueuses orales
EP1937414A4 (fr) * 2005-09-19 2013-01-02 Univ Witwatersrand Jhb Forme pharmaceutique pour muqueuses orales
US12219983B1 (en) 2006-03-15 2025-02-11 Modoral Brands Inc. Compositions for buccal administration
US11129792B2 (en) 2006-03-16 2021-09-28 Modoral Brands Inc. Snuff composition
US11547660B2 (en) 2006-03-16 2023-01-10 Niconovum Usa, Inc. Snuff composition
US10219999B2 (en) 2006-03-16 2019-03-05 Niconovum Usa, Inc. Snuff composition
WO2008127669A1 (fr) * 2007-04-11 2008-10-23 Cephalon, Inc. Compositions pharmaceutiques bicouches lyophilisées et procédés de fabrication correspondant
EP1980245A1 (fr) * 2007-04-11 2008-10-15 Cephalon France Composition pharmaceutique bicouche lyophilisée et ses procédés de fabrication et d'utilisation
JP2012505878A (ja) * 2008-10-14 2012-03-08 マクニール アーベー 複数部分口内剤形及びその使用
EP2361081A4 (fr) * 2008-10-14 2013-08-21 Mcneil Ab Forme posologique intra-orale à parties multiples et son utilisation
EP2361081B1 (fr) 2008-10-14 2016-06-29 McNeil AB Forme posologique intra-orale à parties multiples et son utilisation
WO2010044736A1 (fr) * 2008-10-14 2010-04-22 Mcneil Ab Forme posologique intra-orale à parties multiples et son utilisation
EP2361081A1 (fr) * 2008-10-14 2011-08-31 McNeil AB Forme posologique intra-orale à parties multiples et son utilisation
EP2233134A1 (fr) 2009-03-27 2010-09-29 McNeil AB Dosage intra-buccal multi-portions avec des propriétés organoleptiques
EP2432437A2 (fr) * 2009-05-21 2012-03-28 Bionex Pharmaceuticals LLC Formes pharmaceutiques bicouches et monocouches
EP2432437A4 (fr) * 2009-05-21 2012-12-19 Bionex Pharmaceuticals Llc Formes pharmaceutiques bicouches et monocouches
US10744086B2 (en) * 2009-10-30 2020-08-18 Ix Biopharma Ltd. Fast dissolving solid dosage form
US11975097B2 (en) 2009-10-30 2024-05-07 Ix Biopharma Ltd. Fast dissolving solid dosage form
US12186426B2 (en) 2009-10-30 2025-01-07 Ix Biopharma Ltd. Solid dosage form
US20120219628A1 (en) * 2009-10-30 2012-08-30 Ix Biopharma Pte Ltd Fast dissolving solid dosage form
US20220347095A1 (en) * 2009-10-30 2022-11-03 Ix Biopharma Ltd Solid Dosage Form
US10653686B2 (en) 2011-07-06 2020-05-19 Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
FR2993778A1 (fr) * 2012-07-30 2014-01-31 Pf Medicament Pastilles a cinetiques multiples de liberation de principes actifs
WO2014020039A1 (fr) * 2012-07-30 2014-02-06 Pierre Fabre Medicament Pastilles a cinetiques multiples de liberation de principes actifs
US10213586B2 (en) 2015-01-28 2019-02-26 Chrono Therapeutics Inc. Drug delivery methods and systems
US11400266B2 (en) 2015-01-28 2022-08-02 Morningside Venture Investments Limited Drug delivery methods and systems
US12011560B2 (en) 2015-01-28 2024-06-18 Morningside Venture Investments Limited Drug delivery methods and systems
US10232156B2 (en) 2015-01-28 2019-03-19 Chrono Therapeutics Inc. Drug delivery methods and systems
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US12042614B2 (en) 2017-01-06 2024-07-23 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
CN111989002A (zh) * 2018-03-09 2020-11-24 株式会社Cl制药 无烟香烟用组合物及包含其的口腔溶解膜型无烟香烟
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems
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CN112444466B (zh) * 2019-09-05 2023-02-28 上海新型烟草制品研究院有限公司 一种用于评价口含烟烟碱体外吸收的方法
CN112444466A (zh) * 2019-09-05 2021-03-05 上海新型烟草制品研究院有限公司 一种用于评价口含烟烟碱体外吸收的方法
CN112220756A (zh) * 2020-10-16 2021-01-15 重庆市义力医药科技有限公司 一种尼古丁颗粒组合物及其制备方法

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