《藥劑學》課程雙語教學方法建設的工作進展

1、1,Chapter 5 Capsules,2007.1.28,2,Introduction - The definition of capsules,Capsules are solid dosage forms in which medicinal agents and/or inert substances are enclosed within a small shell of gelatin. Gelatin capsule

2、shells may be hard or soft depending on their composition.Administration route of capsules orally (whole or mixed with food or drink after opening capsules),3,Introduction – Advantages of capsules for oral administra

3、tion,1. conveniently carried2. readily identified3. easily taken4. prescribing flexibility5. Efficiently and productively manufactured6. Packaged and shipped at lower cost and with less breakage7. More stable and h

4、ave a longer shelf-life8. Empty hard gelatin capsules are often used in the extemporaneous compounding of prescriptions.9. Tablets and capsules are sometimes used as the source of a medicinal agent when it is not other

5、wise available.,4,Introduction - Dosage forms that must be left intact,Dosage forms that must be left intact include: enteric coated tablets extended/controlled release dosage forms sublingual or buccal tablets

6、In instances in which a patient is unable to swallow an intact solid dosage form, an alternative product may be employed, such as chewable tablet, instant dissolving tablet, oral liquid, suppository or injection.,5,Type

7、s of capsules,Gelatin capsule shells may be hard or soft depending on their composition.,6,Hard gelatin capsules,The application of hard gelatin capsulesused to manufacture most medicated agentsemployed in clinical tri

8、alsused in the extemporaneous compoundingThe empty capsule shells consist of gelatin, sugar, water, colorants (various dyes), and opaquants遮光劑 (titanium dioxide).,7,Hard gelatin capsules,The main quality control item

9、of gelatin (continuned)viscosity degradation (粘度下降)moisture (水分)transparency (透明度)ash (灰分)pH valueIron: Its concentration depends on the iron content of the water used in its manufacture. ≤15ppm for gelatin used in

10、 soft gelatin capsules.,8,Hard gelatin capsules,Normally, hard gelatin capsules contain between 13 to 16% of moisture.,desiccant (dried silica gel, clay, and activated carbon)→in vitro dissolution→bioavailability.The so

11、lubility property of gelatin:Insoluble in cold water, soften through the absorption of up to ten times its weight of water; soluble in hot water and in warm gastric fluid.Gelatin, being a protein, is digested by proteo

12、lytic enzymes.,9,Two methods used to track the passage of capsules and tablets through the gastrointestinal tract,Gamma scintigraphy(閃爍照相)Heidelberg capsule,10,The manufacture of hard gelatin capsule shells,The shell co

13、nsists of two parts, the capsule body(囊體) and the capsule cap(囊帽).The process of capsule shell production with the peg/pin method: dipping(蘸膠) → drying → stripping(脫模) → trimming(截割) → joining a) The thickness of the

14、 gelatin walls must be strictly controlled. b) The caps are slightly larger in diameter than the bodies.,11,The manufacture of hard gelatin capsule shells,Some improvements to hard gelatin capsule shellscapsule-making

15、 pegs (body-making or cap-making pegs): general rounded shape pegs → tapered pegstapered rims, indentations and locking grooves: straight-walled capsule shell → tapered rim capsule shell with indentations and lo

16、cking grooves (see page 25) a) The tapered rims avoid splitting; b) The indentations prevent premature opening; c) The grooves lock the two capsule parts together after the capsule has been filled.extension

17、capsule cap (CONI-SNAP SUPRO) (see page 26) increase the security of the contents and the integrity of the capsule,12,The manufacture of hard gelatin capsule shells,Tamper-evident sealing and imprintingTamper-evide

18、nt sealing (顯竊啟密封): through various capsule sealing techniquesImprinting which signals will be imprinted on finished capsules? a) names and monograms of the manufacturer b) the assigned national drug code (N

19、DC) number c) other markings making the product identifiable and distinguishable from other products,13,Capsule sizes,How to select capsule size? 1) the amount of fill material to be encapsulated 2) the densit

20、y and compressibility of the fill 3) The final determination largely may be the result of trial. The sizes of empty capsules For human use: 000(the largest), 00, 0, 1, 2, 3, 4, 5 (the smallest) For veterin

21、ary use: Larger capsules are available.,14,Preparation of filled hard gelatin capsules,The general steps of preparation 1) developing and preparing the formulation and selecting the size of capsule. 2) filling the caps

22、ule shells. 3) capsule sealing (optional). 4) cleansing and polishing the filled capsules.,15,Developing the formulation and selection of capsule size,The goal of developing a capsule formulation is to prepare a capsul

23、e withHow to get to the goal? 1) pharmaceutical processing(工藝) 2) pharmaceutical excipient(輔料),16,Developing the formulation and selection of capsule size,The pharmaceutical processing in the preparation of filled har

24、d gelatin capsules 1) blending: → uniform powder mix, uniform drug distribution 2) comminution/milling: 50~100 microns, suitable for a drug of low dose (10mg or greater) 3) micronization: 10~20 microns, suitable for d

25、rugs of lower dose,17,Developing the formulation and selection of capsule size,The pharmaceutical excipient in the preparation of filled hard gelatin capsules 1) diluent/filler: to produce the proper capsule fill volume

26、; to provide cohesion to the powders, e.g. lactose, microcrystalline cellulose and starch 2) disintegrants/disintegration agents: to assist the break-up and distribution of the capsule contents e.g. pregelati

27、nized starch (預膠化淀粉), croscarmellose (交聯(lián)羧甲基纖維素) , and sodium starch glycolate (羥基乙酸淀粉鈉),18,Developing the formulation and selection of capsule size,The pharmaceutical excipient in the preparation of filled hard gelatin c

28、apsules (continued) 3) lubricant or glidant: to enhance the flow properties of the powder mix e.g. fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, or talc #: magnesium stearate, wat

29、er-proofing characteristics, retard penetration of the GI fluids, delay drug dissolution and absorption 4) wetting agents: to facilitate wetting of the dry powder e.g. surfactants, as sodium lauryl sulfate,19,Devel

30、oping the formulation and selection of capsule size,The form of filling material in capsules: 1) powder or granulate 2) pellet mixture 3) paste or wetted mass: the mixture of liquid and an inert powder 4) capsule

31、5) tablet 4 and 5 are employed to separate chemically incompatible agents or to add premeasured (as tablets) amounts of potent drug substances 6) liquids: fixed or volatile oils (locking or sealed gelatin capsules) 7

32、) eutectic mixtures: mixed with a diluent or absorbent to separate the interacting agents and to absorb any liquefied material,20,Developing the formulation and selection of capsule size,The selection of capsule sizeFor

33、 a commercial product: during the product development stageIn the extemporaneous compounding of prescriptions,21,Developing the formulation and selection of capsule size,Examples of filled hard gelatin capsules 1) Tetr

34、acycline capsules Active ingredient: Tetracycline hydrochloride, 250 mg Filler: Lactose Lubricant/glidant: Magnesium stearate Capsule colorants: omitted Cap

35、sule opaquant: Titanium dioxide,22,Filling hard capsule shells,1. The “punch” method suitable for filling a small number of capsules in the pharmacy 1) placing the powder on paper 2) forming the powder mix into a

36、 cake 3) punching the empty capsule body into the powder cake 1) nonpotent drugs: The first filled capsules should be weighed. The other capsules should be weighed periodically. 2) potent drugs: Each capsules shou

37、ld be weighed.,23,Filling hard capsule shells,2. The pouring method suitable for filling a small number of capsules in the pharmacy suitable for granular material,24,3. Hand-operated capsule filling machines consist o

38、f a couple of plates,Filling hard capsule shells,25,SCF-10半自動膠囊充填機,4. Machines for industrial use The process of working: separating the caps from empty capsules → filling the bodies → scraping the excess powder → re

39、placing the caps → sealing the capsules → cleaning the outside of the filled capsules 165,000 capsules per hour,Filling hard capsule shells,26,Capsule sealing,make the capsules tamper-evident (顯竊啟) 1) sealing with a co

40、lored band of gelatin2) heat welding3) Thermally bonding at 40-45℃ with the help of a melting-point-lowering liquid wetting agent4) extemporaneously, by lightly coating the inner surface of the cap with a warm gelatin

41、 solution,27,Cleaning and polishing capsules,Small amount of powder may adhere to the outside of capsules after filling.1) On a small scale, cleaning with a clean gauze or cloth.2) On a large scale, cleaning vacuum,28,

42、Soft gelatin capsules,The definition of soft gelatin capsules Soft gelatin capsules are made of gelatin, glycerin (or a polyhydric alcohol such as sorbitol) and water etc. to hermetically seal and encapsulate liquids, s

43、uspensions, pasty materials, dry powders and even preformed granules, pellets, tablets. They may be manufactured to be oblong, oval or round in shape.The advantages of soft gelatin capsules 1) pharmaceutically elegant

44、 2) easily swallowed by the patient,,,,Turn to 34,Turn to 35,29,Turn to 33,30,Soft gelatin capsules,The pharmaceutical applications of soft gelatin capsules are 1) as an oral dosage form 2) as a suppository dosage form

45、 3) as a specialty package in tube form, for human and veterinary single dose application of topical, ophthalmic, and otic preparations, and rectal ointments.,31,Soft gelatin capsules,The components of soft gelatin caps

46、ules 1) gelatin 2) glycerin or polyhydric alcohol 3) water/moisture 4) preservative 5) colorant 6) markings 7) opaquants 8) Flavors may be added and up to 5% sucrose may be included for its sweetness and to

47、 produce a chewable shell.,32,Preparation of soft gelatin capsules,1. The plate process鋼板模壓法 (using a set of molds) The plates contain die pockets. 1) placing a warm sheet of gelatin on the bottom plate 2) pouring

48、 the liquid-containing medications 3) placing the second sheet of gelatin 4) putting the top plate of the mold into place 5) pressing the mold to form, fill, and seal the capsules simultaneously 6) removing and washi

49、ng the capsule Today, this equipment can no longer be purchased.,33,Preparation of soft gelatin capsules,2. The rotary die process(旋轉(zhuǎn)模壓法 1933, R. P. Scherer) more efficient and productive 1) Liquid gelatin is form

50、ed into two ribbons 2) The two ribbons are brought together 3) Metered fill material is injected between the ribbons 4) These pockets of fill-containing gelatin are sealed,34,,35,Rotary die soft capsule machine,The d

51、ies for production of soft capsule,36,Preparation of soft gelatin capsules,3. The reciprocating die process (往復模壓法 1949, Norton company) is similar to the rotary process in that ribbons of gelatin are formed and used to

52、 encapsulate the fill, but it differs in the actual encapsulating process. 1) A set of vertical dies continually open and close to form rows of pockets in the gelatin ribbons. 2) These pockets are filled with the medi

53、cation and are sealed, shaped, and cut out of the film. 3) The capsules fall into refrigerated tanks which prevent the capsules from adhering to one another.,37,Preparation of soft gelatin capsules,4. The Accogel machin

54、e (1949, Cyanamid comcany) This equipment is unique in that it is the only equipment that accurately fills powdered dry solids.5. Dripping method(滴制法),38,The nature of soft gelatin capsule shell,1) The gelatin is phar

55、macopoeial grade with additional specifications required by the capsule manufacturer. a) Bloom strength: b) viscosity: Generally, 25 to 45 millipoise is acceptable. c) iron: ≤15ppm,39,The nature of soft gelati

56、n capsule shell,2) Plasticizers glycerin or sorbitol or combinations of these The ratio by weight of dry plasticizer to dry gelatin determines the “hardness” of the gelatin shell. 0.4/1 hard 0.6/1 med

57、ium 0.8/1 soft The ratio by weight of water to dry gelatin can vary from 0.7-1.3 to 1.0.3) The color of the gelatin shell,,40,The fill material of soft gelatin capsules,1) liquids a) water-immiscible volati

58、le and nonvolatile liquids b) water-miscible, nonvolatile liquids c) water-miscible and relatively nonvolatile liquids e.g. propylene glycol, isopropyl alcohol d) Liquids that can easily migrate through th

59、e capsule shell cannot be encapsulated into soft gelatin capsules 2) solids (solutions, suspensions, pasty mass, dry powders, granules, pellets, or small tablets.),41,Compendial requirements for capsules,The requirement

60、s for added substances 1) are harmless in the quantities used 2) do not exceed the maximum amounts required to provide their intended effect 3) do not impair the product’s bioavailability, therapeutic efficacy or safe

61、ty 4) do not interfere with requisite compendial assays and tests,42,The container and preservation condition described in USP,containers 1) light resistant container(避光): 2) well-closed container(密閉): 3) tight cont

62、ainer(密封): 4) Hermetic Container (熔封或嚴封):Preservation conditions 1) Freezer: -25 ~ -10 ℃; 2) Cold: 40 ℃; 8) Protection from Freezing: (breakage of the container, loss of strength or potency, destructive altera

63、tion of its characteristics),43,Compendial requirements for capsules,Disintegration test for capsules 1) Method The capsules are placed in the basket-rack assembly, which is repeatedly immersed 30 times per minute i

64、nto a thermostatically controlled fluid at 37 ℃ and observed over the time described in the individual monograph. 2) To fully satisfy the test, the capsules disintegrate completely into a soft mass having no palpably f

65、irm core, and only some fragments of the gelatin shell.,44,Compendial requirements for capsules,Dissolution test for capsules 1) The apparatus, dissolution media and test is the same as that for uncoated and plain coate

66、d tablets. 2) Generally, when a dissolution test is applied to an existing capsule product, the disintegration test is unnecessary.,45,Compendial requirements for capsules,Weight variation and content uniformity show th

67、e uniformity of dosage units. Weight variation Wcapsule – Wemptied shell = Wcontent 10 capsules labeled amount or average amount, ±10% 1) For hard capsules #1: Wcapsule should match Wemptied shell. 2

68、) For soft capsules #1: evaporating the washing solvent over 30 mins #2: avoid uptake or loss of moistureContent uniformity The amount of active ingredient should be within the range of 85% to 115% of the label amo