Download Hydroxypropyl Methyl Cellulose (HPMC)

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Neuropsychopharmacology wikipedia , lookup

Environmental persistent pharmaceutical pollutant wikipedia , lookup

Environmental impact of pharmaceuticals and personal care products wikipedia , lookup

Orphan drug wikipedia , lookup

Psychopharmacology wikipedia , lookup

List of off-label promotion pharmaceutical settlements wikipedia , lookup

Neuropharmacology wikipedia , lookup

Pharmaceutical marketing wikipedia , lookup

Pharmacogenomics wikipedia , lookup

Bad Pharma wikipedia , lookup

Tablet (pharmacy) wikipedia , lookup

Compounding wikipedia , lookup

Biosimilar wikipedia , lookup

Pharmacognosy wikipedia , lookup

Drug design wikipedia , lookup

Drug interaction wikipedia , lookup

Sol–gel process wikipedia , lookup

Medication wikipedia , lookup

Prescription costs wikipedia , lookup

Pharmaceutical industry wikipedia , lookup

Drug discovery wikipedia , lookup

Pharmacokinetics wikipedia , lookup

Nicholas A. Peppas wikipedia , lookup

Transcript
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 2.786
Volume 3, Issue 9, 551-566.
Research Article
ISSN 2278 – 4357
HYPROMELLOSE – A CHOICE OF POLYMER IN EXTENDED
RELEASE TABLET FORMULATION
Dipti Phadtare*, Ganesh Phadtare , Nilesh B*, Mahendra Asawat*
* Pacific Academy for Higher Education and Research, Faculty of Pharmacy, Udaipur, India.
Article Received on
25 June 2014,
Revised on 20 July
2014,
Accepted on 13 August 2014
ABSTRACT
Hydroxypropylmethylcellulose (HPMC) also know as hypromellose, is
largely in used cellulose ether in the development of hydrophilic
matrices. Hypromellose provides the release of a drug in a controlled
manner, effectively increasing the duration of release of a drug to
*Correspondence for Author
Dipti Phadtare
prolong its therapeutic effect. This review provides a current insight
Pacific Academy for Higher
into hypromellose and its applicability to hydrophilic matrices in order
Education and Research,
to highlight the basic parameters that affect its performance. Topics
Faculty of Pharmacy, Udaipur,
covered include the chemical, thermal and mechanical properties of
India.
hypromellose, hydration of the polymer matrices, the mechanism of
drug release and the various models used to predict the kinetics and
mechanism of drug release from the HPMC matrices. This review also provides the
maximum potency of hypromellose used in various dosage form and current patent status
review of hypromellose as a release controlling polymer in extended release matrix systems.
Keywords: Hydrophilic matrix; HPMC; release mechanism; mathematical models; patent
Hydroxypropyl methylcellulose ethers belong to an extensive family of white to off-white,
odorless, water soluble polymers that bind, retain water, thicken, form films, lubricate, and
much more. Synonym for hydroxypropyl methylcellulose (HPMC) is Hypromellose. It is a
semi synthetic, inert, viscoelastic polymer, used as an excipient and controlled-delivery
component in oral medicaments, found in a variety of commercial products.
Hypromellose is a methylcellulose modified with a small amount of propylene glycol ether
groups attached to the anhydroglucose of the cellulose. It is a methyl and hydroxypropyl
mixed ether of cellulose. The product contains, calculated on dry basis, 19 % to 30 % of
www.wjpps.com
Vol 3, Issue 9, 2014.
551
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
methoxyl (-OCH3) groups and 3 % to 12 % of hydroxypropyl (-OCH2CHOHCH3) groups.
The limits for the types of Hypromellose (hydroxypropyl methylcellulose) set forth in the
table 1. [1-2]
Table 1
Substitution Type
1828
2208
2906
2910
Methoxy (%)
Minimum
Maximum
16.5
20.0
19.0
24.0
27.0
30.0
28.0
30.0
Hydroxypropyl (%)
Minimum
Maximum
23.0
32.0
4.0
12.0
4.0
7.5
7.0
12.0
Table 2: The critical attributes of Hypremellose described in some of pharmacopoeias
are listed in below table.
Attribute
Definition
Labeling
Identification (A)
Identification (B)
Identification (C)
Identification (D)
Identification (E)
Viscosity, Method 1
Viscosity, Method 2
Attribute
pH
Heavy Metals
Loss on Drying
Residue on Ignition
Assay
JP
+
+
+
+
+
+
+
+
+
JP
+
+
+
+
+
 Legend: + will adopt and implement;
EP
+
+
+
+
+
+
+
+
+
EP
+
+
+
+
+
USP
+
+
+
+
+
+
+
+
+
USP
+
+
+
+
+
will not stipulate
 Nonharmonized attributes: Packaging and Storage
 Specific local attributes: Appearance of solution (EP), Description (JP), Limit of glyoxal
(EP) [2]
Chemistry
Hypremellose have the polymeric backbone of cellulose, a natural carbohydrate that contains
a basic repeating structure of anhydroglucose units (See figure below). During the
manufacture of cellulose ethers, cellulose fibers are heated with a caustic solution which in
turn is treated with propylene oxide, yielding hydroxypropyl substitution on the
www.wjpps.com
Vol 3, Issue 9, 2014.
552
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
anhydroglucose units of methyl ether of cellulose. The fibrous reaction product is purified
and ground to a fine, uniform powder.
Fig. 1. Chemical structure of HPMC.
The substituent R represents either a –CH3, or a –CH2CH(CH3)OH group, or a hydrogen
atom.
Hypromellose possess varying ratios of Hydroxypropyl and Methyl substitution which in
turns determine the organic solubility as well as thermal gelation temperature of aqueous
solution. The extent of substitution is designated by weight percentage of substituent group
attached to the ring; know as „degree of substitution‟ (D.S.). A lower D.S. results in lower
solubility and is only soluble in caustic solution. The letter „E‟, „K‟, „J‟ and „F‟ identify the
different Hypromellose grade product with respect to their properties. The suffix „S‟ denotes
„surface treated, „G‟ denotes „Granular grade‟ while „CR‟ denotes „Controlled Release‟
grade. In „E‟, „F‟ and „K‟ grade products the substitution is major constituents as mentioned
in below table while in case of „J‟ it is about 50% of the total substitution.[1]
Table 3: Degree of Substitution for different grades of Hypromellose
Grade
E
K
F
J
Methoxyl D.S.
Methoxyl %
1.9
1.4
1.8
1.3
29
22
28
18
www.wjpps.com
Hydroxypropyl Molar
Substitution
0.23
0.21
0.13
0.82
Vol 3, Issue 9, 2014.
Hydroxypropyl
%
8.5
8.1
5.0
27
553
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Properties
General properties common to the Hypremellose are listed below. Individual type exhibits
these properties to varying degrees and may have additional properties that are desirable for
specific applications.
1) Apparent density: 0.25~0.70g/cm 3 (Typical:0.5g/cm 3 );
2) The refractive index of 2% aqueous solutions at 20°C is for all types: nD20 =1.336
3) For Hypromellose powders, the following values are used
a. Specific heat, Cp = 0.28 BTU/lb-F
b.Thermal conductivity, k = 0.028 BTU/hr-ft-F
4) Approximate values for specific gravity are given for some concentration below
a. 1% solution: 1.0012
b.5% solution: 1.0117
c. 10% soluton: 1.0245
5) Surface tension: Surface tensions range from 42 to 56 mN/m. The surface tension of water
is 72 mN/m; a typical surfactant has a surface tension of 30 mN/m.
6) Dissolubility: dissolve in water and some solvent. Such as, the suitable proportion of
ethanol/ water, propanol /water. Its aqueous solution provides surface activity and high
transparence and stable properties. Various products have different gel temperatures.
Solubility changes with viscosity. Lower the viscosity is, higher the solubility is. Different
types of Hypremellose have different properties. Its dissolution is not subject to pH.
7) With the reduction of methoxy content, gel point rises, solubility in water and surface
activity decrease.
The most critical property of Hypromellose is a viscosity. The viscosity of an aqueous
solution of a Hypromellose is proportional to the molecular weight or chain length of the
specific Hypromellose product used. Commercial designations of Hypromellose products are
based on viscosity values determined in water at 20°C, with a concentration of 2%
Hypromellose. The table below provides further information regarding the commercial
viscosity designation. All the products mentioned in table are Premium EP grades, which
means they meet the compendial requirements of the US and European Pharmacopoeias.
www.wjpps.com
Vol 3, Issue 9, 2014.
554
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
*CR – Controlled Release Grades
** LH - Product with lower Hydroxypropyl content specification 7%-9%
Table 4: Hypromellose Commercial grade with respective viscosity
USP Designation
2910
2910
2910
2910
2910
2910
2910
2910
2906
2208
2208
2208
2208
2208
2208
2208
2208
2208
2208
2208
Hypromellose Commercial grade
E 3 Premium LV
E 5 Premium LV
E 6 Premium LV
E 15 Premium LV
E 50 Premium LV
E 4M Premium
E 4M Premium CR
E 10M Premium CR
F 4M Premium
K 3 Premium LV
K 100 Premium LV
K 100 Premium LV CR*
K 100 Premium LV LH**
K 100 Premium LV LH CR
K 4M Premium
K 4M Premium CR
K 15M Premium
K 15M Premium CR
K 100M Premium
K 100M Premium CR
Viscosity (cP)
3
5
6
15
50
4000
4000
10000
4000
3
100
100
100
100
4000
4000
15000
15000
100000
100000
Hypromellose Dissolving Methods
1) Product with surface treatment(s) can be added in tap water directly and can disperse
quickly through agitating. The solution pH value can be adjusted to the range of 8-9 by
adding in alkali in form of ammonia and Na2CO3. By agitating the solution viscosity can be
increased.
2) Product without surface treatment can swell and disperse in hot water with temperature
higher than 85ºC. Usually it is dissolved by the following methods. Take about 1/5~1/3 of the
needed hot water and agitate so that the added product will swell completely. Then add in the
remained water, which can be hot or cold, agitate to the appropriate temperature and the
product can dissolve completely. As to dissolve HPMC by hot water method, it is very
important to cool the mixture down. To dissolve the product completely and form ideal
transparent solution, the temperature is dependant upon the type of HPMC.
www.wjpps.com
Vol 3, Issue 9, 2014.
555
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
3) Dispersing by dry mixing, i.e., the product can be mixed with other powder substance
homogeneously first, and then tap water is added in, so that the product will dissolve quickly
without any gel.
4) Wetting with organic solvent. Disperse the product in organic solvent first or wet the
product by organic solvent and then add the mixture into hot water or add in hot water, which
could also dissolve the product efficiently. The organic solvent could be ethanol or ethandiol
[3].
GRAS status
Based on the information provided by Dow, as well as other information available to FDA,
the agency has no questions at this time regarding Dow's conclusion that HPMC-ESP is
GRAS under the intended conditions of use. The agency has not, however, made its own
determination regarding the GRAS status of the subject use of this ingredient. As always, it is
the continuing responsibility of Dow to ensure that food ingredients that the firm markets are
safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to
GRN 000213, as well as a copy of the information in this notice that conforms to the
information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is
available for public review and copying on the homepage of the Office of Food Additive
Safety. http://www.cfsan.fda.gov/~lrd/foodadd.html
Pursuant to proposed 21 C.F.R. 5 170.36(c), on the basis of scientific procedures in
accordance with 21 C.F.R. 5 170.30, that the use of its hydroxypropyl methylcellulose
(HPMC) product is generally recognized as safe (GRAS) when used in food for multiple
technical effects, including as a source of dietary fiber. The enclosed Notification is a revised
version of the GRAS Notice that was submitted by Dow Chemical. The Food and Drug
Administration (FDA) is responding to the notice, dated September 20, 2006, that you
submitted on behalf of the Dow Chemical Company (Dow) in accordance with the agency's
proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances
Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on
September 22, 2006, filed it on September 27, 2006, and designated it as GRAS Notice No.
GRN 000213.
www.wjpps.com
Vol 3, Issue 9, 2014.
556
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
The subject of the notice is hypromellose, a propylene glycol ether of methylcellulose
containing 16-31.5 percent methyl groups and 2-32 percent hydroxypropyl groups. For the
purpose of this letter, FDA refers to the subject of the notice as "HPMC - expanded
substitution pattern" (HPMC-ESP). The notice informs FDA of the view of Dow that HPMCESP is GRAS, through scientific procedures, for use in food in general, including meat and
poultry products, at intake levels up to 20 grams per person per day (g/p/d). The detail
information of GRAS status of hypremellose is uploaded on the link below
http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GR
ASListings/ucm153856.htm
Inactive Ingredient Database
According to 21 CFR 210.3(b)(8), an inactive ingredient is any component of a drug product
other than the active ingredient. Only inactive ingredients in the final dosage forms of drug
products are in this database.
The Inactive Ingredients Database provides information on inactive ingredients present in
FDA-approved drug products. This information can be used by industry as an aid in
developing drug products. For new drug development purposes, once an inactive ingredient
has appeared in an approved drug product for a particular route of administration, the inactive
ingredient is not considered new and may require a less extensive review the next time it is
included in a new drug product.
Hypromelose is also included in the inactive ingredient database. Following table depict
some of the approved drug product in which it is used as a inactive ingredient with its route
of administration and maximum potency. [4-5] The table mainly summarizes the use of
Hypromelose as release retarding inactive ingredient. For other applications, information is
provided on the link below.
1. http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm
2. http://www.fda.gov/Drugs/InformationOnDrugs/ucm075230.htm)
3. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelo
pedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationAND
www.wjpps.com
Vol 3, Issue 9, 2014.
557
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Table 5:
Inactive Ingredient
Route;Dosage form
UNII
Z78RG6M2N2
Z78RG6M2N2
2.771MG
HYPROMELLOSE
2208 (15000 MPA.S)
ORAL; CAPSULE, SUSTAINED ACTION
ORAL; CAPSULE, SUSTAINED ACTION, HARD
GELATIN
ORAL; TABLET
ORAL; TABLET, CONTROLLED RELEASE
ORAL; TABLET, EXTENDED RELEASE
ORAL; TABLET, SUSTAINED ACTION
ORAL; TABLET, SUSTAINED ACTION,
COATED
ORAL; TABLET, SUSTAINED ACTION, FILM
COATED
Maximum
Potency
336MG
Z78RG6M2N2
Z78RG6M2N2
Z78RG6M2N2
Z78RG6M2N2
86MG
7.8MG
320MG
480MG
Z78RG6M2N2
94MG
Z78RG6M2N2
200MG
ORAL; TABLET, EXTENDED RELEASE
2F7T07H9ZD
175MG
ORAL; TABLET, EXTENDED RELEASE
VM7F0B23ZI
54MG
ORAL; CAPSULE, DELAYED ACTION
ORAL; CAPSULE, ENTERIC COATED PELLETS
ORAL; CAPSULE, EXTENDED RELEASE
ORAL; CAPSULE, SUSTAINED ACTION
ORAL; CAPSULE, SUSTAINED ACTION, HARD
GELATIN
ORAL; TABLET, CONTROLLED RELEASE
ORAL; TABLET, DELAYED ACTION
ORAL; TABLET, DELAYED ACTION, ENTERIC
COATED
ORAL; TABLET, ENTERIC COATED
PARTICLES
ORAL; TABLET, EXTENDED RELEASE
ORAL; TABLET, ORALLY DISINTEGRATING,
DELAYED RELEASE
ORAL; TABLET, SUSTAINED ACTION
ORAL; TABLET, SUSTAINED ACTION,
COATED
ORAL; TABLET, SUSTAINED ACTION, FILM
COATED
288VBX44JC
288VBX44JC
288VBX44JC
288VBX44JC
33.42MG
13.82MG
10.6MG
10.88MG
288VBX44JC
4.772MG
288VBX44JC
288VBX44JC
20MG
4.47MG
288VBX44JC
19MG
288VBX44JC
445MG
288VBX44JC
150MG
288VBX44JC
7MG
288VBX44JC
250MG
288VBX44JC
6MG
288VBX44JC
54MG
HYPROMELLOSE
2208 (60000 MPA.S)
HYPROMELLOSE
2208 (80000-120000
CPS)
HYPROMELLOSE
2910 (15000 MPA.S)
HYPROMELLOSE
2910 (4000 MPA.S)
HYPROMELLOSE
2910 (50 MPA.S)
HYPROMELLOSE
2910 (6 MPA.S)
www.wjpps.com
ORAL; CAPSULE, EXTENDED RELEASE
27MG
ORAL; CAPSULE, EXTENDED RELEASE
54MG
ORAL; TABLET, EXTENDED RELEASE
Vol 3, Issue 9, 2014.
0WZ8WG20P6 92.794MG
558
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Application
Hypromellose is a water-soluble polymer derived from cellulose, the most abundant polymer
in nature. It is used as thickener, binder, film former, and water-retention agent.
Hypromellose is also function as suspension aids, surfactants, lubricants, protective colloids
and emulsifiers. In addition, solutions of HPMC, thermally gel, a unique property that plays a
key role in a surprising variety of applications. Such a kind of valuable combination of
properties is not available in any other water-soluble polymer.
Hydroxypropyl methylcellulose Ethers are highly efficient, often yielding optimum
performance at a lower concentration than that required with other water-soluble
polymers.The broad range of Hydroxypropyl methylcellulose is certainly one reasonit is used
successfully in so many different applications. There are many different chemical types and
each is available in different grades, physical forms, and viscosities. Available viscosity
grades range from 3 to over 200,000 mPas.
Hydrophilic matrix systems designed with water-soluble polymers, such as Hypromellose,
were first introduced in the early 1970‟s. Since then, development work has concentrated on
controlled release technology, and many types of advanced polymers and techniques have
become available. The hydrophilic matrix system is the simplest sustained release technology
for oral dosage forms, consisting essentially of a drug and a water soluble, highly viscous
polymer. It does not require any other excipient. Recent advances in this hydrophilic matrix
system have allowed more controllable and reproducible drug release by controlling the
chemical and physical properties of the polymer. Hypromellose is especially suitable for this
application, and provides a genuine consistency in the final products.
Hydrophilic Matrices
The principle of drug release from hydrophilic polymers is due to hydration and swelling
(Figure 1) During the initial formation of the gel layer a preliminary burst of drug release is
typical. The extent of the burst is dependent on the solubility of the drug substance and how
rapidly the polymer can hydrate to form the gel layer, which is influenced by the polymer
chemistry and particle size. Reducing the particle size of the polymer reduces the burst
release and eventually slows down the rate of release (this is because the hydration rate of the
gel increases and gel layer forms more rapidly). Once the gel layer has formed, it controls
the release rate of the drug substance, principally by diffusion control for high solubility
www.wjpps.com
Vol 3, Issue 9, 2014.
559
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
drugs, erosion control for low solubility drugs or by a combination of diffusion and erosion.
The polymer viscosity controls the rate of erosion.
Initial Tablet
Water insoluble drug is released through
tablet erosion
Water soluble drug is released by
diffusion through the tablet core
Gel layer
expands
Water continue to permeate the
core and the hydrated outer layer dissolves
Figure 1
Drug Release from a Hydrophilic Matrix
The most commonly used polymers for hydrophilic matrices are Hydroxypropyl methyl
cellulose (Hypromellose or HPMC). Hydrophilic matrices based on HPMC are the most
common and have the widest application across a range of drug substance properties. When
formulating with HPMC, consideration needs to be given to the following factors, which
affect the dissolution profile
 HPMC content
 HPMC to drug ratio
 HPMC viscosity
 Drug solubility
 HPMC substitution
 HPMC particle size
 Drug particle size
 Diluent particle size
 Diluent solubility
The above factors should be incorporated into a DOE to fully understand their effect in
controlling the dissolution rate of each compound. Detailed information regarding the use of
HPMC for controlled release of drugs in hydrophilic. Within each substitution type and
www.wjpps.com
Vol 3, Issue 9, 2014.
560
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
viscosity, additional sub grades maybe available e.g. CR (tighter control on polymer particle
size) low humidity and low substitution, and these should be selected with care. [6]
It is possible to combine different polymer chemistry and viscosities to further control the
release profile. However, caution is recommended as this may result in a combination of
release mechanisms which may be difficult to interpret in-vitro or in-vivo.
Examples of suitable HPMC grades for modified release formulation development are listed
in Table 6
Table 6: HPMC Grades Suitable for Controlled Release
USP
Designation
2910
2910
2910
2910
Methocel Product
Shinetsu Product
E4M Premium EP
Metolose 60SH
E4M Premium CR EP N/A
Metolose 60SH
E10M Premium CR EP
2208
K100 LV EP
Metolose 90SH
2208
K4M Premium EP
Metolose 90SH
2208
K4M Premium CR EP Metolose SR 90SH
2208
K15M Premium EP
Metolose 90SH
2208
K15M Premium CR EP
2208
K100M Premium EP
Metolose 90SH
2208
K100M Premium CR Metolose SR 90SH
EP
1. cP (cps) is equivalent to milli Pascal second
Nominal Voscosity
cP1
4000
4000
10000
10000
100
4000
4000
15000
15000
100000
100000
Matrix Tablet Formulations
Application
Benefits
Low Solubility Drugs
Fast polymer hydration to
form gel layer; non-ionic
Med to High Solubility Drugs
Fast polymer hydration to
form gel layer; non-ionic
Typically Used
METHOCEL Cellulose
Ethers
E50LV, K100LV, K100LV
CR
K4M, K15M, K100M, E4M,
E10M, K4MCR, K15MCR,
K100MCR, E4MCR,
E10MCR
Release Mechanism
The overall drug release mechanism from HPMC based pharmaceutical devices strongly
depends on the design (composition and geometry) of the particular delivery system. Drug
molecules are released at the surface, as well as diffusing into the inner swelling polymer (a
www.wjpps.com
Vol 3, Issue 9, 2014.
561
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
dissolution process) and then diffusing outwards through the swelling polymer and finally
through the outer gel layers.
In the GIT HPMC matrix undergoes:
1) surface wetting (rapid)
2) surface swelling (slow process)
3) surface erosion (ongoing)
4) surface gel formation (ongoing)
5) gradual inner polymer swelling
6) ongoing outer gel erosion
Erosion front
Swelling front
Diffusion front
Figure 2: Schematic illustration of a swellable hypromellose-based matrix during drug
release.
The three distinct moving fronts are indicated. At all times the dissolved drug profile extends
from the diffusion to the erosion front and the water profile from the swelling to the erosion
front (i.e. the entire gel layer).
At the beginning of the process, steep water concentration gradients are formed at the
polymer/ water interface resulting in water imbibition into the matrix. Water acts as a
plasticizer and reduces the glass transition temperature of the system; the polymer chains
undergo the transition from the glassy to the rubbery state. Due to the imbibition of water
HPMC swells, resulting in dramatic changes of polymer and drug concentrations, and
increasing dimensions of the system.
www.wjpps.com
Vol 3, Issue 9, 2014.
562
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Upon contact with water the drug dissolves and (due to concentration gradients) diffuses out
of the device. With increasing water content the diffusion coefficient of the drug increases
substantially.
In the case of poor water-solubility, dissolved and non-dissolved drug coexist within the
polymer matrix. Non-dissolved drug is not available for diffusion. In the case of high initial
drug loadings, the inner structure of the matrix changes significantly during drug release,
becoming more porous and less restrictive for diffusion upon drug depletion.
Depending on the chain length and degree of substitution of the HPMC type used, the
polymer itself dissolves more or less rapidly.
Active drug is released in the gastrointestinal tract via contributions from different release
mechanisms. Initially surface erosion of the tablet face occurs and water imbibes into the
polymer matrix. Slow direct erosions of the polymer matrix and erosion, after transient
swelling, at the surface with the formation of a gel layer occur. Diffusion release of the drug
from the polymeric matrix results, through the swelling gel layer, with concomitant ongoing
polymer surface erosion. At the end of the drug release, the matrix is completely dissolved,
suggesting that the overall drug release time is controlled by the tablet erosion. [8-11]
Kinetics of Drug Release
In order to understand the mechanism and kinetics of drug release from hypromellose, the
results of the in-vitro drug release can be fitted with various kinetic equations like
Zero order
Qt = Q0 + K0t ……………………….(1)
where Qt is the amount of drug dissolved in time t, Q0 is the initial amount of drug in the
solution (most times, Q0 = 0) and K0 is the zero order release constant.
First order
log(Qt) = log(Q0) + K1t /2.303………(2)
where Qt is the amount of drug dissolved in time t, Q0 is the initial amount of drug in the
solution and K1 is the first order release rate constant.
Higuchi model
Qt = KH√t ………………………….(3)
KH is the Higuchi‟s release constant
www.wjpps.com
Vol 3, Issue 9, 2014.
563
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Hixson-Crowell
Q01/3 - Qt1/3 = KHCt ………………….(4)
where Q0 is the initial amount of drug in the pharmaceutical dosage form, Qt is the remaining
amount of drug in the pharmaceutical dosage form at time „t‟ and KHC is a constant
incorporating the surface–volume relation.
KorsemeyerPeppas
Korsmeyer et al (1983) derived a simple relationship which described drug release from a
polymeric system Eq. (5). To find out the mechanism of drug release, first 60% drug release
data was fitted in Korsmeyer–Peppas model:
Mt/M∞ = KKPtn…………………………(5)
Where Mt / M∞ is fraction of drug released at time t, KKP is the rate constant and n is the
release exponent. The n value is used to characterize different release mechanisms as given in
table 7 [7]
Table 7
Thin Film
0.5
0.5 <n<1.0
1.0
Exponent (n)
Cylinder
0.45
0.45<n<0.89
0.89
Sphere
0.43
0.43<n<0.85
0.85
Drug release mechanism
Fickian diffusion
Anomalous transport
Case-II transport
Patent status
Hypromellose is a choice of polymer used as release controlling polymer in extended release
matrix system. Due to its various properties as mentioned, various pharmaceutical companies
used it in variety of dosage form to prolong the release of drug to extend the life span of the
various
drugs.
The
current
patents
approved
in
various
countries
for
hydroxypropylmethylcellulose in extended release matrix system are about 12000. The
following table illustrates the importance of this polymer. [12]
Table 8: Number of patents approved in different patent offices
Countries
ARIPO (African Regional intellectual property organization)
European Patent Office
Israel
PCT (Patent corporation Treaty)
South Africa
www.wjpps.com
Vol 3, Issue 9, 2014.
Number of patent
6
1681
165
9205
419
564
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Table 9: Number of patents approved for companies
Main Applicant
THE PROCTER & GAMBLE COMPANY
KIMBERLY-CLARK WORLDWIDE, INC.
ABBOTT LABORATORIES
MONDOBIOTECH LABORATORIES AG
ALZA CORPORATION
CELGENE CORPORATION
HYSEQ, INC.
ISIS PHARMACEUTICALS, INC.
NOVARTIS AG
PROCTER & GAMBLE
Number of patent
280
203
156
135
115
78
77
76
76
74
2500
2000
1500
Publication Year
Number of Patent
1000
500
0
Publication Year
1
2
3
4
5
6
7
8
9
10
11
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Number of Patent 496
591
705
907 1045 1010 1166 1142 916
994
697
CONCLUSIONS
Effort to exemplify this polymer over the last four decades has multiplied, yet many
challenges remain unanswered. To date, many diverse techniques have been used to study the
mechanism of drug release from hypromellose matrices. As expertise evolves, there will be
further methods that can characterize hypromellose in a non-invasive manner. Hypromellose
is growing ever more popular as the controlled release polymer of choice.
REFERENCES
1. Dow Commercial Information (2002) Using methocel cellulose ethers for controlled
release of drugs in hydrophilic matrix systems. The Dow Chemical Company, USA, pp
1–36
2. http://en.wikipedia.org/wiki/Semisynthesis
www.wjpps.com
Vol 3, Issue 9, 2014.
565
Phadtare et al.
World Journal of Pharmacy and Pharmaceutical Sciences
3. Ashland Specialty Ingredients (2011) Benecel, Hydroxypropyl cellulose – for personal ,
USA, pp 1–28
4. http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm
5. http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm
6. Maderuelo, A. Zarzuelo, J. Lanao, Critical factors in the release of drugs from sustained
release hydrophilic matrices, J. Control. Release, 2011; 154: 2–19.
7. P. Costa, J.M. Sousa Lobo, Review Modeling and comparison of dissolution profiles,
Eur. J. Pharm. Sci, 2001; 13: 123 –133.
8. J. Siepmann, N.A. Peppas, Modeling of drug release from delivery systems based on
hydroxypropyl methylcellulose (HPMC), Adv. Drug Deliv. Rev, 2001; 48: 139–157.
9. J. Siepmann, H. Kranz, R. Bodmeier, N.A. Peppas, HPMC-matrices for controlled drug
delivery: a new model combining diffusion, swelling and dissolution mechanisms and
predicting the release kinetics, Pharm. Res, 1999; 16: 1748–1756.
10. J. Siepmann, K. Podual, M. Sriwongjanya, N.A. Peppas, R. Bodmeier, A new model
describing the swelling and drug release kinetics from hydroxypropyl methylcellulose
tablets, J. Pharm. Sci, 1999; 88: 65–72.
11. Korsmeyer, R.W., Gurny, R., Doelker, E., Buri, P., Peppas, N.A., “Mechanisms of solute
release from porous hydrophilic polymers,” J. Pharm. Sci., 1983; 15: 25-35 .
12. http://patentscope.wipo.int/search/en/result.jsf?currentNavigationRow=next&prevCurrent
NavigationRow=1&query=Hydroxypropyl methyl cellulose and extended release matrix
system&office=&sortOption=Pub Date Desc&prevFilter=&maxRec=11476
www.wjpps.com
Vol 3, Issue 9, 2014.
566