Hard
`Capsules
`
`DEVELOPMENT
`& TECHNOLOGY
`0 O O
`EDITED BY
`
`K. RIDGWAY
`
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`

`DEVELOPMENT
`& TECHNOLOGY
`0; ® Q
`EDITED BY
`
`This book will fill a gap in the literature
`on capsule technology and is expected to
`become a standard reference on the
`subject. It documents the development of
`the gelatin capsule from its inception in
`the early nineteenth century, through to
`its present day use. The mass production
`of high quality capsules has required the
`development of complex machinery and
`the book gives a thorough account of all
`aspects of the manufacture of gelatin
`capsules, and their filling on hand, semi-
`automatic and automatic machinery. A
`description is given of the methods and
`equipment used in the following finishing
`processes associated with the production
`of hard capsules: Filling with pellets,
`pastes and liquids; Printing on the
`capsule; Weighing; Cleaning and
`Inspecting for faults. There are nearly
`150 illustrations contained within the
`text. Literature references are listed at the
`end of each chapter and an extensive
`classified bibliography of approximately
`1300 entries at the end of the book covers
`the literature on both hard and soft
`gelatin capsules.
`This work will be essential reading for all
`those involved in the development,
`manufacture and testing of hard capsules.
`
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`

`
`
`DEVELOPMENT
`& TECHNOLOGY
`
`'
`
`EDITED BY‘
`
`K. RIDGWAY
`
`CHAPTERS
`The History of the Gelatin Capsule
`Gelatin: Structure and Manufacture
`Gelatin: Physical and Chemical
`Properties
`Gelatin Additives, Substitutes, and
`Extenders
`Capsule Standards
`The Manufacture of Hard Gelatin
`
`
`
`Capsules
`Powder Characteristics for Capsule
`Filling
`The History of Capsule-filling
`Machinery
`The Mechanical Operations of Filling
`Hard Capsules
`Capsule—fi11ing Machinery
`Capsule Types, Filling Tests, and
`Formulation
`Capsule Handling Systems
`Drug Release from Capsules
`BIBLIOGRAPHY OF CAPSULES
`
`DIRECTORY OF MANUFACTURERS
`
`INDEX
`
`.A
`
`
`
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`

`PROPEKW OF
`
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`
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`

`
`
`3'53
`
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`
`%.
`
`,"
`
`
`
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`

`HARD‘ CAPSULES
`
`DEVELOPMENT AND TECHNOLOGY
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`
`
`O__.
`
`-
`
`HARD CAPSULES
`
`DEVELOPMENT AND TECHNOLOGY
`
`Edited by
`
`K. Ridgway
`
`London
`
`THE PHARMACEUTICAL PRESS
`1987
`
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`

`
`
`Copyright © 1987 by The Pharmaceutical Society of Great Britain
`
`Copies of this book may be obtained through any good bookseller, or in any case of difficulty, direct from
`the publisher or the publisher’s agents:
`The Pharmaceutical Press
`(publications division of The Pharmaceutical Society of Great Britain)
`1 Lambeth High Street, London SE1 7JN, England
`Australia
`The Australian Pharmaceutical Publishing Co. Ltd
`35 Walsh Street, West Melbourne 3003
`Canada
`McAinsh & Co. Ltd
`2760 Old Leslie Street, Willowdale, Ontario M2K 2X5
`
`_
`
`i
`
`Japan
`Maruzen Co. Ltd
`3-10 Nihonbashi 2—chome, Chuo-ku, Tokyo 103
`New Zealand
`The Pharmaceutical Society of New Zealand
`124 Dixon Street,‘PO Box 11-640, Wellington
`U. S.A.
`Rittenhouse Book Distributors, Inc.,
`511 Feheley Drive, King of Prussia, Pennsylvania 19406
`
`International Standard Book Number (ISBN): 0 85369 159 2. All rights reserved. No part of this publication may
`be reproduced, stored in a retrieval system, or transmitted in any form or by any means—electronic, mechanical,
`photocopying or otherwise—without the prior written permission of the copyright holder. Typeset, printed and
`bound in Great Britain by The Bath Press, Bath BA2 3BL, Avon.
`
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`

`

`K. Ridgway, BA, BSc, PhD, Dip Chem Eng, C Chem, FRSC, C Eng, FIChemE
`Formerly Senior Lecturer, School of Pharmacy, University of London
`
`Editor
`
`Contributors
`
`G. C. Cole, BA, CEng, MIChemE
`Staff Specia1ist—Pharmaceuticals, Davy McKee, London
`
`B. E. Jones, MPharm, MPS
`Advisor, Customer Technical Services, Elanco Qualicaps, Lilly Industries Ltd, Basingstoke, Hampshire
`
`R. T. Jones, BSC
`Director of Research and Development, Croda Colloids Ltd, Widnes, Cheshire
`
`-
`J. M. Newton, BPharm, PhD, FPS
`Professor of Pharmaceutics, School of Pharmacy, University of London
`
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`

`
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`

`
`
`Contents
`
`Preface
`
`CHAPTERS
`
`1
`
`2
`
`’
`
`3
`‘
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`The History of the Gelatin Capsule
`B. E. Jones '
`
`Gelatin: Structure and Manufacture
`R. T. Jones
`
`Gelatin: Physical and Chemical Properties
`R. T. Jones
`
`Gelatin Additives, Substitutes, and Extenders
`B. E. Jones
`’
`
`Capsule Standards
`B. E. Jones
`
`The Manufacture of Hard Gelatin Capsules
`B. E. Jones
`
`Powder Characteristics for Capsule Filling
`G. C. Cole
`
`'
`
`The History of Capsule-filling Machinery
`G. C. Cole
`
`The Mechanical Operations of Filling Hard Capsules
`G. C. Cole
`
`Capsule-filling Machinery
`G. c. Cole
`
`Capsule Types, Filling Tests, and Formulation
`G. C. Cole
`
`Capsule Handling Systems '
`G. C. Cole
`
`Drug Release from Capsules
`J. M. Newton
`
`_
`
`‘
`
`BIBLIOGRAPHY OF CAPSULES
`B. E. Jones and J. M Newton
`
`DIRECTORY OF MANUFACTURERS
`
`INDEX
`
`"
`
`'
`
`ix
`
`1
`
`13
`
`31
`
`49
`
`61
`
`68
`
`80
`
`87
`
`92
`
`104
`
`165
`
`176
`
`195
`
`205
`
`301
`
`302
`
`
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`
`
`Preface
`
`The gelatin capsule was originally devised about
`150 years ago as a- means of masking the unplea-
`sant taste of certain liquid medicaments. These
`capsules were crudely hand-made. In the interven-
`ing years, a sophisticated technology for the mass
`production of high quality capsules has been devel-
`oped, and the capsule has become a popular alter-
`native to tablets as a dosage form.
`Information on the techniques used in the pro-
`duction of capsules has not been readily available
`because much of it has been confined to research
`
`papers published in a variety of technical journals.
`This book has been designed to fill the need for
`a concise description of the history, manufacture,
`and filling of hard gelatin capsules. The text is sup-
`ported by nearly 150 illustrations.
`The book traces the history of capsule making
`and filling. The original method of forming cap-
`sules by dipping moulds into gelatin solution has
`not changed, but the mass production of high
`quality capsules has required the development of
`complex machinery. After manufacture, capsules
`must be printed with a name and code number
`for
`identification purposes,
`and then filled.
`Numerous automated systems havebeen devised
`for filling capsules with powders, although manual
`methods may still be used for small batches for
`experimental purposes.
`In addition, pellets,
`pastes, and liquids can now be filled into hard cap-
`sules. Capsules which have been filled must then
`be check-weighed, cleaned and inspected for
`faults. The methods and equipment used in all
`these processes are described.
`Gelatin is almost the perfect substance for mak-
`ing capsules and two chapters cover the essential
`details‘of the structure, manufacture, and physical
`and chemical properties of gelatin. However,
`although gelatin is ideal for the purpose, other
`materials which might be used as substitutes or
`extenders have been investigated. There are also
`various additives which may be used to modify
`the properties of gelatin.
`' Capsules must be manufactured to a high quality
`
`the legislative requirements con-
`because of
`sequent upon the need for therapeutic effective-
`ness and patient acceptability. In addition, the
`manufacturing process requires high standards of
`inspection and control in order to avoid stoppages
`and breakdowns due to defective capsules. Gui-
`dance is given on pharmacopoeial, manufacturing,
`and other standards.
`
`Powders which are to be filled into hard capsule
`shells must have flow properties which allow accur-
`ate dosing at high speed. Moreover, the formula-
`tion of the powder must take into account the
`release of the drug (the bioavailability) after inges-
`tion of the capsule. The parameters which must
`be considered in the formulation of powders for
`filling into capsules are described and discussed.
`The text contains many literature references
`relevant to the subject matter: these are listed at
`the end of each chapter. In addition, an extensive
`structured Bibliography at the end of the book
`contains over 1300 references on all aspects of cap-
`sule technology.
`It has not proved possible to include an up-to-
`date account of the development and manufacture
`of soft gelatin capsules, but appropriate compari-
`son with hard capsules will be found in several
`chapters, and relevant references are included in
`the Bibliography.
`
`Acknowledgments
`
`The expenses of writing and editing this volume
`were underwritten by Merck Sharp and Dohme
`Ltd, Hoddesdon, Hertfordshire and their support
`is gratefully acknowledged.
`‘
`The assistance of manufacturers in allowing
`publication of illustrations and details of their
`machinery and capsules is duly acknowledged.
`The general editorial staff of the Department of
`Pharmaceutical Sciences of The Pharmaceutical
`
`Society of Great Britain, who assisted in checking
`and preparing the manuscript for press, are ack-
`nowledged with thanks.
`
`
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`
`
`Chapter 1
`
`The History of the Gelatin Capsule
`
`B. E. Jones
`
`The word ‘capsule’ in ‘the English language is de-
`rived from the Latin word ‘capsula’, which means
`a small box or container. The word occurs in many
`scientific disciplines, ranging from-anatomy, as an
`enclosing membrane, and botany, as a descriptive
`word for fruit, to astrophysics, as a space vehicle.
`In pharmacy, ‘capsule’ has been used to describe
`a glass ampoule (e.g. amyl nitrite capsules) and
`also as a name for a protective cap over the stopper
`of a bottle of medicine. In more recent times, ‘cap-
`sule’ has been used primarily to describe a solid
`oral dosage form which consists of a container,
`usually made of gelatin, filled with a medicinal
`substance. The word can be used to refer either
`to the gelatin container itself or to the whole
`object, container plus drug. In this book it will
`be used chiefly to mean a single-dose medicine
`container.
`
`There are many forms of capsule and they can
`be divided into two main categories which in cur-
`rent usage are described by the adjectives ‘hard’
`and ‘soft’. The hard gelatin capsule consists of two
`separate parts, each a semi-closed cylinder in
`shape, one part being called the ‘cap’, having a
`slightly larger diameter than the other, which is
`called the ’body’ and which is longer. The cap fits
`closely over the body to form a sealed unit. The
`soft gelatin capsule is a one-piece container which
`has a variable shape, and, due to its method of
`manufacture, may be either seamed, along its axis,
`or seamless. The adjectives hard and soft are
`sometimes applied to soft gelatin capsules, and
`in this context the terms refer to whether the cap-
`sule wall contains glycerol or other plasticiser
`whichmakes it soft and elastic, if included, or hard
`and rigid,
`if omitted. In current manufacturing
`practice all one-piece gelatin capsules are soft and
`elastic.
`'
`
`The Invention of the Gelatin Capsule
`
`The gelatin capsule was invented in the early nine-
`teenth century as a result of the need to mask
`
`the obnoxious taste of many of the medicinal sub-
`stances which were in vogue at that time. One
`important such drug was the oleoresin of copaiba,
`which is extremely nauseating when taken by
`mouth. It was used in the treatment of venereal
`
`disease, the incidence of which appears to have
`been high as a result of the Napoleonic wars and
`the associated social unrest
`in Europe. Many
`unsuccessful attempts. were made to overcome this
`taste problem. Mixtures with the standard phar-
`maceutical vehicles, aromatic waters, essential
`oils, honey, and syrups were made, but to no avail.
`All the culinary arts were employed, even going
`so far as the making of a ‘copaiba custard’. The
`first successful solution to the problem was the
`invention of the capsule, which covered the indivi-
`dual dose in a bland tasteless film of gelatin, ena-
`bling it
`to be swallowed easily and without
`interfering with its activity.
`The first recorded patent for a gelatin capsule
`was French Patent 5648, granted in Paris on 25th
`March 1834 to Dublanc and Mothes. The idea was
`quickly acclaimed and its use spread rapidly both
`inside and outside France. This rapid spread might
`have been caused either by simultaneous discovery
`by other workers, or, what is more probable, by
`the fact that it filled an undoubted need and was
`a good commercial proposition. In 1835, the year
`following the first patent, capsules were being
`manufactured in places as far apart as Berlin and
`New York (Anon., Pharm. Era, 1896a; Schlenz-_
`Casel, 1897).
`inventor of the gelatin capsule
`The actual
`appears to have been Mothes. In the preamble
`to the first addition to the patent of Mothes and
`Dublanc, granted in December 1834, it was stated
`that Mothes was a pharmacy student, and so was
`under the legal age to obtain his pharmacy dip-
`loma; in order to present the patent he became
`associated with Dublanc, who was already an
`established pharmacist. The addition to the patent
`is further described as being made by Mothes ‘in
`
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`
`
`2
`
`The History of the Gelatin Capsule
`
`his personal name and in his own private interest’.
`In 1837 Mothes applied for an extension to the
`period of validity "of
`the original patent. The
`French Academy in reviewing his case noted that
`he had broken off his association with Dublanc
`
`(Planche and Gueneau de Mussy, 1837), and
`granted to him a ten-year extension as the sole
`proprietor of the invention. Dublanc’s name was
`soon omitted in the many references to capsules
`made in the contemporary literature.
`No copy of the original patent seems to be avail-
`able. However, the first addition to the patent des-
`cribed the method of manufacture in full, said that
`‘It was not without its own inconveniences’ and
`went on to describe improvements. The capsules
`were formed on moulds which were small round
`
`pouches made of soft leather tied to a small long-
`necked metal funnel by a waxed string. The
`moulds were filled with mercury to make them
`firm,
`then dipped into - a solution of gelatin,
`removed and placed in a heated box at 40° to dry.
`To remove the capsules from the moulds the mer-
`cury was emptied" out and the gelatin shape was
`then carefully taken off the mould. To prevent
`the gelatin adhering to the moulds they were
`covered in ‘baudruche’, gold-beater’s skin. As a
`result the capsules had walls consisting of two
`layers. Mothes considered that this method was
`expensive and not capable of producing capsules
`of a large enough size. The improved method of
`the first addition was to use solid moulds, in the
`shape of an elongated sphere, and made of bur-
`nished brass to prevent oxidation. They were
`dipped into concentrated solutions of flavoured
`and sweetened gelatin, then placed upright on a
`special board and allowed to cool. The capsules
`were removed before they were completely dry
`and finished off by_being placed on a sieve in a
`slightly heated room. They were carefully filled
`with the balsam and then sealed with a drop of
`gelatin solution.
`In France, capsules acquired an immediate
`popularity. An idea of the extent of this can be
`gained from the quantities “of materials which
`Mothes was reported as having used in his process:
`in 1835, 3500kg of gelatin and in 1836, 1500 kg
`of copaiba balsam (equivalent to 750000 doses)
`(Herpin,_ 1837). To purchase this large quantity
`of copaiba he had to travel to London because
`Paris was unable to supply his needs. His business
`was extended by increasing the number of types
`of oil filled into capsules and also by supplying
`empty capsules to pharmacists.
`
`Capsules rapidly achieved official recognition.
`When Mothes presented his invention to the Aca-
`démie Royale de Médecine they paid him a high
`compliment, saying that he had rendered an
`immense service to science and humanity (Anon. ,
`Chemist Drugg., 1889). In 1837 Dr Ratier made
`an entry in the ‘Dictionnaire de Médecine et de
`Chiru_rgie pratiques’ to the effect that capsules
`were a means of directly administering copaiba
`without in any way altering its virtues.
`In 1838 Mothes ceased to supply empty capsules
`to the pharmaceutical
`trade and, as a, result,
`several attempts were made to overcome his
`patent, which he was rigorously enforcing. In the
`previous year, when the Economic Committee of
`the French Academy investigated his application
`for a patent extension, they found he was employ-
`ing twenty workmen in his business (Herpin,
`1837). They surmised that if the patent was not
`renewed there would be a rush of other companies
`into the field. They held the capsule in such high
`regard that it was proposed that it should be
`brought to the attention of other industries, and
`Herpin suggested to the Academy that because
`of the importance of capsules they should be filled
`with native resinous medicines that were similar
`
`to copaiba, such as turpentine oil. This would have
`a favourable economic effect and would also be
`
`of strategic importance. He obviously suggested
`this because of the very successful English naval
`blockade during the Napoleonic wars, which were
`then still fresh in people’s memories. In this year
`a method was published for masking the flavour
`of cubeb, copaiba, and other nauseous materials
`using gelatin, but not as a capsule as defined in
`the patent (Garot, 1838). The drugs were first
`formed into standard pill masses, each of which
`was mounted on a pin and then dipped into a gela-
`tin solution. After drying, the pins were removed
`and the resulting holes sealed with a drop of gela-
`tin. Garot stated that he had devised this method
`
`only because of Mothes’s refusal to sell empty cap-
`sules.
`
`For some reason, the method mainly quoted in
`the literature as being used by Mothes was the
`cumbersome one described in the first patent. This
`may have been deliberately brought about for
`commercial reasons, or may have been due to the
`fact that French patents at that time were hand-
`written documents and it would have been necess-
`
`ary to attend the patent office in person to read
`them. The standard source for information was
`
`a report on the original patent by Cottereau pub-
`
`
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`The Invention of the Gelatin Capsule
`
`3
`
`lished in the journal Traité de Pharmacologie. As
`a result, several workers published ‘new methods’
`for making capsules using metal moulds.
`In 1846 in the Journal de Pharmacie et de
`
`Chimie, Giraud claimed a method-_ using iron
`moulds (Giraud, 1846). The editor in a footnote
`to the article pointed out
`that
`this infringed
`Mothes’s patent. In 1850,
`in the same journal,
`there was a report on Mothes’s improved method
`of making capsules. using metal moulds which,
`rather strangely, described the method used by
`him in his first patent addition fifteen years pre-
`viously. Alpers, in a history of capsules published
`in 1896, upbraided Mothes for taking Giraud’s
`idea and claiming it as his own (Alpers, 1896a).
`In the United States of America the first men-
`tion of capsules in the pharmaceutical literature
`was in 1835 in the American Journal of Pharmacy,
`which published an abstract of the paper by Cot-
`tereau describing their method of manufacture
`(Cottereau, 1835-6). In the same journal
`two
`years
`later, Alfred Guillou of Philadelphia
`reported the results of a series of experiments on
`capsules (Guillou, 1837). These enabled him to
`make capsules which looked identical to those
`made in France, so much so that they could not
`be distinguished from them. In fact he sold them
`as being of French origin. He used metallic ovoid
`moulds, mounted on tin dishes, a method exactly
`as described in Mothes’s addition to his patent.
`Alpers credited Guillou with being the first to sug-
`gest this method of manufacture. No practical use
`appears‘ to have been made of this invention and
`there is no further record of Guillou’s association
`
`with capsules.
`The first American capsule business was started
`in New York in 1836 by H. Planten, a Dutchman
`who had emigrated there in 1835 (Alpers, 1896a).
`He was described as using French manufacturing
`methods, sellinghis capsules as ‘Mothes’s cap-
`sules’ and packing them with directions for use
`in both English and French. The medical profes-
`sion in America had very rapidly accepted that
`capsules were an excellent method of adminis-
`tration for copaiba and that France was the source
`of high quality material. It was many years before
`capsules of American origin were sold openly and
`made with American-manufactured gelatin.
`In the German-speaking states the invention
`appears to have been first reported by Buchner
`(1837). He described Mothes’s capsules as copaiba
`balsam covered in a bubble of glue, and said that
`the method of making them was unknown. Later
`
`the same year, a Munich physician, Dr Feder, dis-
`closed the secret of their manufacture to those
`
`interested (Schlenz—Casel, 1897). He described a
`method similar to that of Mothes,‘ using solid
`moulds of hard wood or, later, iron, which were
`lubricated by dipping in soap spirit. Feldhaus
`(1912), commenting on the spread of capsule
`usage in Germany, referred to the fact that there
`was no uniform patent law at that time and it was
`only in Prussia, where patents were "examined
`carefully, that the patent of Mothes and Dublanc
`was upheld. The first large-scale manufacture in
`Germany is credited to a Berlin pharmacist, J. E.
`Simon, also in 1837. Schlenz-Casel remarked in
`1897 that the rapid spread of capsules in Germany
`was due to the high profit margin in their manufac-
`ture; in that year there were 13' capsule-—factorie’s
`listed in the Pharmaceutical Calendar.
`.
`In Britain, although capsules appear to have
`been widely used from an early-date,‘the only
`references to their manufacture were reports from
`other countries. The first. was an? abstract in the
`
`Lancet in 1840 of a paper by Desfontenelles from
`the Journal de Chimie. This described a method
`
`of making ‘gelatinous capsules.’ by an adaptation
`of theoriginal Mothes and Dublanc patent but
`using arather strange mould, the swimming blad-
`der of a_tench or other fish from 5 to 7 inches
`long. This was tied by a ligature to a copper tube,
`inflated, greased with lard, then dipped in a hot
`solution of gelatin made to the formula of Garot.
`When set, the capsule was removed by deflating
`the bladder.
`.
`I
`
`The first mention in the Pharmaceutical Journal
`came in 1843 with thetranslation of an article by
`Adolph Steege, Court Apothecary at Bucharest,
`called ‘On the formation of the gelatinous capsules
`of Balsam of Copaiba’. The moulds were made
`of iron, mounted on ‘a wooden plate, and after
`lubrication with almond oil were dipped in gelatin
`solution. When the gelatin had set, the capsules
`were trimmed to theright length, carefully pulled
`off the moulds-and-. driedon a loose hair sieve.
`The balsam was filledinto them using a glass drop‘-
`per tube and they were sealed by carefully dipping
`them into gelatin solution. Steege claimed that
`capsules could _be made elastic by adding sugar
`to the gelatin solution, and transparent by using
`isinglass instead of gelatin.
`.
`,
`In France, the commercial success of the gelatin
`capsule stimulated many workers to try to devise
`ways of overcoming Mothes’s patent, which he was
`enforcing with litigation. Mothes’s precise methods
`
`
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 18/326
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`QUALICAPS EX. 2001 - 18/326
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`§ 123.I
`
`.
`j.
`
`
`
`4
`
`The History of the Gelatin Capsule
`
`were apparently only known to a few people,
`which led to his improved process, using metallic
`moulds, being reinvented several times. Sinninoir
`from Nancy in 1841 suggested the use of wax
`moulds mounted on metallic pins (Schlenz-Casel,
`1897). The moulds were removed from the capsule
`by heating them and melting the wax, a tedious
`process which did not prove viable. Moulds for
`dipping were best made from metal, and there was
`no success in the search for alternative materials.
`
`Improved Methods of Manufacture of One-piece
`Gelatin Capsules
`
`Many inventors applied themselves to devising
`improved mechanical
`systems.
`In 1844, Viel
`obtained a French patent for _a method of making
`and filling the capsule on the same piece of appara-
`tus. He formed a tube of gelatin by dipping hollow
`cylindrical moulds. The gelatin tubes could be
`pulled off the moulds and at the same time could
`have liquid medicaments pumped into them
`through the centre of the moulds. The filled tubes
`were cut up into capsules using a special pair of
`pincers developed from the castration scissors
`used by farmers (Schlenz-Casel, 1897). Mothes
`and his new partner Lamouroux claimed infringe-
`ment, and a panel of three experts considered the
`case. Two of them considered that Viel’s process
`was an infringement of Mothes’s patent, but the
`third, Professor Chevallier of the School of Phar-
`macy, Paris, thought Viel’s method was signifi-
`‘ cantly different from Mothes’s because of the use
`of a single mould for both making and filling the
`capsules. He complained also of Mothes’s restric-
`tive practices in refusing to sell empty capsules
`and trying to obtain a monopoly in the supply of
`copaiba capsules. The Chambre du Conseil ac-
`cepted the minority opinion, and gave judgement
`in favour of Viel. __ Mothes and Lamouroux
`appealed against the decision, but at the same time
`purchased Viel’s process from him for 37000
`francs. Their appeal was subsequently rejected.
`In Italy, also in 1844, Pegna made capsules by
`casting_in moulds instead of by dipping. He used
`moulds which consisted of a closely-fitting pair of
`brass plates with the forms of the capsules on their
`inside surfaces. A gelatin solution was poured into
`the moulds to form the capsule. A similar process
`was patented in France in 1846 by Lavalle, a doc-
`tor, and Thévenot, a pharmacist, from Dijon
`(French Patent 3906). Their capsule moulds were
`a pair of hexagonal copper or iron plates in which
`suitable cavities had been formed and a plate
`
`which acted as a guide to locate the moulds accu-
`rately together. Their capsule mass -was a solution
`of gum, sugar, gelatin, and a little honey which
`they claimed was more soluble than the mixture
`used by Mothes. It was cast into thin sheets, and
`a sheet was laid on top of one of the plates, so
`that it took up the shape of the cavities. The medi-
`cament was placed in the hollows. A second sheet
`was placed on the first and the second plate was
`put into position by means of the guide plate. The
`whole assembly was placed in a press and the cap-
`sules stamped out. These capsules were much
`more regular in shape than Mothes’s, and they
`later became known as ‘perles’. The inventors
`made capsules containing liquids, such as copaiba,
`cod-liver oil, and turpentine oil, and powders such
`as quinine sulphate and rhubarb. In an addition
`to this patent in 1850 in the names of Clertan and
`Lavalle, the capsules were coated with syrup and
`presented as a bonbon.
`Mothes and Lamouroux, using some of Viel’s
`ideas, obtained a patent in December 1846 for a
`‘machine to prepare and manufacture a large
`number of Mothes capsules’ (French Patent 4780).
`Their machine was a rotary die type apparatus,
`a forerunner to the main process in use today.
`Gelatin ribbons were passed between two sets of
`rollers. The first set positioned the ribbons. The
`second set had capsule-shaped cavities in their sur-
`faces so that as the rollers came together capsules
`were cut out of the ribbons. They called this
`machine a ‘Capsulateur Mécanique’, but do not
`appear to have used it because Mothes obtained
`another patent for making capsules by dipping in
`1850 (Anon. , J. Pharm. Chim. , Paris, 1850). Their
`problem was probably the difficulty in filling the
`capsules during manufacture. However, Viel, who
`had obviously not relinquished his interest in cap-
`sules, obtained a patent in 1859 for a ‘Capsulateur
`Viel’ (French Patent 43022). He used large rib-
`bons of gelatin which were passed between rollers
`turned by hand in a device similar to a clothes
`mangle. The liquid to be filled was held in a pear-
`shaped flask and was delivered into the nip of the
`rollers just where the capsules were formed.
`Berthiot,
`a Parisian pharmacist, patented
`another method in 1860 (French Patent 43 963).
`Gelatin solution was forced through an annular
`orifice to form a tube which was continuously filled
`with liquid from a concentric tube in the centre.
`The gelatin tube was chilled to set it and then
`formed into capsules by passing it between two
`engraved rollers. This process is the forerunner
`
`E
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2001 — 19/326
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2001 - 19/326
`
`

`

`
`
`of that used to make seamless soft gelatin capsules
`today. Many other patents were granted about this
`time for improvements to the system for making
`capsules (Thuret, 1943) which is indicative of the
`commercial success of the capsule as a dosage
`form.
`
`Other workers explored the use of alternative
`materials from which to prepare capsules to defeat
`Mothes’s limitations on trade. Substances were
`
`chosen on the basis of alleged improvements in
`performance in vivo over gelatin, perhaps antici-
`pating the present-day interest in drug release. In
`1843, Savaresse, father and son, and Douillet
`obtained a patent for the manufacture of organic
`capsules called ‘Savaresse’ (French Patent 15 212).
`The elder Savaresse was a manufacturer of musical
`
`strings and they used the catgut process to prepare
`thin membranes from the small intestines of sheep.
`These were cut into small lengths, dipped into sul-
`phurous acid solution as a preservative, and then
`placed over capsule-shaped moulds. When dry
`they were removed and filled, the open end being
`closed with a knot of fine thread and sealed with
`
`a drop of gelatin. The inventors argued that a gela-
`tin capsule dissolved too quickly, perhaps even
`in the mouth, and as a result patients could exper-
`ience ‘nauseous eructations’. They claimed that
`the membrane passed through the stomach unaf-
`fected and disintegrated only in the intestines. This
`description of an enteric product was made 40
`years before the generally-acknowledged inventor
`of this idea, Unna, published it (Durnez, 1921).
`In 1845 a patent for the same membrane capsule
`was granted in Britain to Evans and Lescher
`(Anon. , Pharm. J. , 1845-6). Alpers refers to them
`as French pharmacists. The same journal also pub-
`lished a letter from a Dr Garrod reporting that
`a trial of membrane capsules showed that they pro-
`tected his patients from the taste of copaiba with-
`out detracting from its efficacy. A few months
`later, in the same journal, Dr William Acton wrote
`a paper entitled ‘On the best means of disguising
`the taste of nauseous medicines’,
`in which he
`stated that capsules were the best modern method
`of giving nauseous liquids and that membrane cap-
`sules were an improvement over gelatin ones
`because the latter were often too thin and burst
`
`on swallowing. A