International Journal of Pharmaceutics, 18 (1984) 201-205 (cid:9)
`Elsevier
`
`201
`
`1JP 00607
`
`The effect of anionic surfactants on the release of
`chlorpheniramine from a polymer matrix tablet
`
`P.B. Daly, S.S. Davis an.: J.W. Kennerley *
`Department of Pharmacy, University of Nottingham. University Park, Nottingham NG7 2RD and
`* R.P. Scherer b4 Frankland R0124 Blagrove, Swindon, Wiltshire SN5 8YS (U.K)
`(Received January 27th, 1983)
`(Modified version received July 14th, 1983)
`(Accepted July 19th, 1983)
`
`Matrix tablets have long been used to obtain sustained drug delivery and it was
`Higuchi (1963) who first presented a detailed mathematical analysis of such release.
`Bamba et al. (1979) further developed the mechanisms of release fri. matrix
`systems that swell at the tablet periphery to form a gel which acts as a barrier to
`drug diffusion.
`It is becoming increasingly apparent that the viscosity characteristics of the
`polymers, that go to make the matrix tablet, are of great importance in determining
`the final release properties of the dosage form. Huber and Christensen (1968), when
`investigating the release of a tracer (tartrazine) from two hydroxypropyl methylcel-
`lulose (HPMC) matrix tablets, found that the higher viscosity grade HPMC released
`the tracer at a significantly slower rate than the lower grade. More recently Nakano
`et al. (1983) studied the release of theophylline from hydroxypropyl cellulose tablets;
`here again the rate .of release was slower for the higher viscosity grades. The
`sustained drug release from these two systems is achieved by the polymer swelling to
`a gel-like consistency at the tablet periphery and forming a barrier to drug diffusion.
`Harwood and Schwartz (1982), when investigating the release of pilocarpine from
`ophthalmic HPMC matrix preparations also found the release to be slower from the
`higher viscosity grades. The present study firstly concerns the release of chlo-
`rpheniramine from tablets made from 4 different viscosity grades of HPMC and
`secondly the effect of an anionic surfactant, sodium lauryl sulphate (SLS), on drug
`release from HPMC tablets.
`Tablets of nominal weight, 300 mg containing 45 mg chloipheniramine maleate,
`mere prepared using an instrumented Manesty F3 machine, fitted with 10 mm
`diameter flat-faced punches and die, at an upper punch compaction pressure of 175
`
`Correspondence; S.S. Davis, Department of Pharmacy. University of Nottingham, University Park.
`Nottingham NO? 2RD. U.K.
`
`( 378-5173/K4/S03.00 C 1984 Elsevier Science Publishers S.V.
`
`Exhibit 1038
`ARGENTUM
`IPR2018-00080
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`000001
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`202
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`MN • m-2. Tablets outside the weight range 290-310 mg were rejected. The dissolu-
`tion of the drug from the tablets was monitored using either a manual sampling or
`continuous flow •tec'que In the case of the manual method 1000 ml of 0.1 N
`hydrochloric acid was introduced into 6 vessels of an Erweka DT-D6 USP method 1
`dissolution apparatus with a rotation speed of 100 rpm. Samples were periodically
`withdrawn for spectrophotometric assay at 265 nm (Cecil Instruments, Model
`CF292) and then returned to the dissolution vessel. The continuous flow technique
`used the same dissolution apparatus but the dissolution medium was pumped
`through a spectrophotometer (Kontron, Model Uvikon 810) fitted with an automatic
`6 cell changer. A microprocessor (Commodore Business Machines, Model 8032)
`interfaced to the spectrophotometer gave digital absorbance values for each cell. The
`two sampling techniques have been shown to give equivalent results. The dissolution
`data were plotted as the percent remaining in the tablets against time.
`Viscosity determinations on 2% solutions of four HPMC grades were carried out
`at 37°C using a U-tube viscometer (Grade D) (British Pharmacopoeia 1980, method
`1).
`The dissolution profiles of chlorpheniratnine tablets made from the different
`viscosity grades of HPMC are shown in Fig. I. From the time for 50% release (Tso%)
`values shown in Table 1 it can be seen clearly that the drug dissolution from the
`tablets is significantly slower for the higher viscosity grade HPMCs. This fits with
`the findings of Huber and Christensen (1968) and Nakano et al. (1983) as described
`earlier.
`A substance that could affect the viscosity of an HPMC may be of use in
`changing the release of drug from tablets made from this material. It has been
`reported extensively in the literature (for example, Saito 1960) that the viscosity of
`
`% Drug remaining in tablet
`
`Fig. 1. The release of chlorphenirarnine from different viscosity grade HPMCs. Key: Methocel E5. a:
`Methocel (cid:9)
`Methocel E50, 0; Methocel E4M, ¤,
`
`Time (tiours1
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`000002
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`203
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`non-ionic polymers can be increased by the addition of anionic surfactants. A
`similar type of effect has been reported more recently by Walker and Wells (1982)
`who found that a combination of the anionic sodium carboxymethyl-cellulose with
`cellulose produced a synergistic increase in viscosity. Thus the effect of the anionic
`surfactant sodium lauryl sulphate (SLS), on a modified HPMC (Synchron), used
`commercially to manufacture sustained release tablets, was studied to determine
`whether a more sustained action could be obtained through the incorporation of a
`surfactant.
`Firstly, the effect of SLS on the viscosity of a 2% Synchron solution at 37°C was
`studied. Table 1 shows that the viscosity is enhanced by the addition of SLS. Table 1
`also shows, for comparative purposes, the viscosity data obtained under the same
`conditions, for the four HPMCs used abs-we.
`To study the effect of SLS on the release of drug from HPMC tablets three
`different batches of Synchron were manufactured to contain 5, 10 and 15% surfac-
`tant. Fig. 2 shows that tablets containing 15% SLS give a zero-order in vitro release
`profile with a considerable retardation of release rate. From Fig. 2 it is evident that
`the retardation is dependent upon the amount of surfactant incorporated in the
`formulation.
`It is possible that this retardation is not due to the increased gel viscosity at the
`tablet periphery, but due to complex formation between the cationic ehlorphenira-
`mine and the anionic surfactant. However, this is unlikely to be the principal
`mechanism by which a more sustained action is achieved since similar release effects
`were obtained with anionic drugs. Changes in tablet porosity in the presence of
`
`TABLE 1
`
`A COMPARISON BETWEEN THE RELEASE OF CHLORPHENIRAMINE AND THE VISCOSITY
`GRADE
`
`HPMC
`
`Methocel E5 b
`Methocel EIS
`Methocel E50
`Methocel E4M
`Synchron'
`Synchron 2% + 0.25%
`sodium lauryl rilphate
`Synchron 2% + 0.5%
`sodium lauryl sulphate
`
`Viscosity'
`(centistokes)
`
`3.5
`9.9
`25.2
`2 662.0
`21.5
`
`45.7
`
`70.0
`
`Time for 50%
`release (T5o% )
`(h)
`
`1.1
`1.3
`1.7
`2.9
`1.7
`
`° Viscosity of a 2% solution (except where indicated) determined at 37°C.
`Methocel supplied by Colorcon Ltd., Kent.
`Synchron supplied by Pharmax Ltd., Kent.
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`204
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`100
`
`cn 60
`
`L.
`
`•_
`E
`La' 40
`cn
`L
`
`4'. 20
`
`A
`
`A
`
`•
`
`0
`
`a
`
`O
`
`0
`
`1 (cid:9)
`
`2 (cid:9)
`
`3 (cid:9)
`Time (hours)
`Fig. 2. The effect of sodium lauryl sulphate (SLS) on the release of chlorpheniramine from Synchron.
`Key: no SLS, a; 5 SLS, 0; 10% SLS, •; 15% SLS. n.
`
`4 (cid:9)
`
`5 (cid:9)
`
`6
`
`surfactant are also unlikely to account for the change in release rates because
`compaction pressures in the range 50-200 MN • m-2 do not significantly alter the
`release rates from HPMC tablets (Daly, 1984). A series of non-ionic surfactants, Brij
`35, Myrj 59, Pluronic F88 and the cationic surfactant cetrimide, were also investi-
`gated. No change in the release rate of chlorpheniramine was noted, indicating thht
`the observed behaviour is restricted to anionic surfactants.
`It can be concluded that the anionic surfactant, SLS, is able to modify the release
`profiles of drugs from HPMC tablets giving an increased duration of release. It is
`considered that the mechanism involved is related to the ability of anionic surfac-
`tants to bind to non-ionic polymers acting to increase the viscosity.
`It is appreciated that SLS at high concentrations is not suitable for oral adminis-
`tration but mother anionic surfactant, dioctyl sodium sulphosuccinate, has been
`incorporated into HPMC tablets. The dissolution of this formulation has been
`assessed in human subjects using gamma scintigraphy. Again the surfactant gave a
`more sustained action, the results from this study have been reported elsewhere
`(Davis et al., 1983).
`
`Acknowledwments
`
`The authors would like to thank Kendal Pitt for technical assistance, Pharmax
`Ltd. for studentship to P.B.D. and Colorcon Ltd. for supplying the different grades
`of Methoc,,I.
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`References
`
`British Pharmacopoeia. Vol. IL Her Majesty's Stationery Office, 1980, Appendix VH., p. A77.
`Bamba, M., Puisieux. F., Marty, J.P. and Carstensen, .I.T., Release mechanisms in gel forming sustained
`release preparations. Int. J. Pharts„ 2 (1979) 307-315.
`Davis, &&, Daly. P.B.. Kennerley, J.W. and Bradbury. D.M., The role of gamma scintigraphy to
`simultaneously monitor the in vivo dissolution of drug from two formulations. J. Pharm. Pharmacol.,
`(1983) in press.
`Daly, P.D.. Studies on the release of drugs from matrix tablets. Ph.D. Thesis, University of Nottingham,
`1984.
`Harwood. R.J. and Schwartz, J.B.. Drug release from compression molded films: preliminary studies with
`pilocarpine. Drug Dev. Ind. Pharm., 8 (1982) 663-682.
`Huber, H.E. and Christensen, G.L., Utilisation of hydrophilic gums for the control of drug substance
`release from Tablet Formulations. II. Influence of tablet hardness and density on dissolution
`behaviour. J. Pharm. Sci., 57 (1968) 164-166.
`Higuchi, T.. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid
`drugs dispersed in solid matrices. J. Pharm. Sci., 52 (1963) 1145-1149.
`Nakano. M., Ohmani. N., Ogata, A., Sugimato, K... Tabino, Y., lwaoku, R. and ICartilliko, J.. Sustained
`release of theophylline from hydroxypropyloellulaie tablets. J. Pharm. Sci., 72 (1983) 378-380.
`Saito, S., Binding of surfactants by polymers. J. Colloid Sci., 15 (1960) 283-286.
`United States Pharmacopoeia, Mack Publishing, Easton, Vol. XX, 1980, p. 959.
`Walker, C.V. and Wells, IL, Rheological synergism between ionic and non-ionic cellulose gums. Int. J.
`Pharm., 11 (1982) 309-322.
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