In recent years, a spurt of research and development has been conducted involving
a wide range of protein therapeutics. Although, the administration of proteins
by injection is the most effective mean of delivery in vivo but patient
tolerance of multiple injections is very poor. In addition, the administration
of drugs via injection routes is a skilled job and requires training;
this skill and training may not always be transferable to patients. In cases
where protein drugs have a life-saving role, the administration by the injection
route is highly accepted. However, in cases where protein drugs are just one
of several possible therapies for long use, injections of proteins and peptides
are unlikely to be accepted by the patients. Therefore, alternative routes of
protein and peptide delivery need to be explored and developed. Among proteins,
oral delivery of insulin has received the widest attention, yet no currently
available oral insulin preparation exists. Other alternatives may include the
buccal, nasal, oral, pulmonary, rectal and ocular routes. Without exception,
these routes are less effective than the parenteral routes of administration.
However, these are still far more attractive than the parenteral routes because
they offer convenience to patients. Out of these all, oral route is particularly
attractive because it is the most convenient, quick and is self-contained. Watts
and co-workers proposed drug delivery system for colonic delivery of insulin
which releases insulin from proximal colon. The improved bioavailability of
insulin results from a combined effect of absorption promoters, dispersing agents
and by-pass of liver (Watts and Illum, 2001).
In normal physiology, the 100% insulin that is secreted by the pancreas enters
portal circulation where liver uses an estimated 50-80% and rest enters systemic
circulation from the liver (Agarwal and Khan, 2001).
Even colon targeted or buccal-spray insulin do not reach liver like natural
pancreatic insulin. The ratio of plasma insulin in portal circulation versus
that in peripheral circulation may vary from 2- to 3-fold (Porksen
et al., 2002; Arbit and Kidron, 2009). The
physiological hypoglycaemic effect of insulin is due to suppression of hepatic
glucose production that is enhanced by the increase in glucose use caused by
lower insulin levels in peripheral circulation (Satake et
al., 2002; Camacho et al., 2004). So
if we make oral insulin to pass through liver, the real physiological effect
can be produced which is not possible with colon targeted insulin.
The need to increase absorption rate of insulin across brush-border mucosa
appears less as it is absorbed across mucosa normally by passive transport (transcellular
endocytosis) (Ziv and Bendayan, 2000). No doubt various
polymers have increased insulin bioavailability significantly by paracellular
pathway (Tuesca et al., 2008). Increasing absorption
by permeation enhancer through paracellular way have also resulted into damage
to integrity of cells as normal insulin insertion into the lumen of rat duodenum
and colon presented evidences of stress or slight degeneration of cellular membrane
(Cano-Cebrian et al., 2005). The need is to protect
insulin from luminal enzymes as it is known that upon ingestion, insulin is
subjected to acid-catalyzed degradation in the stomach, luminal degradation
in the intestine and intracellular (cytosolic) degradation but not to enzymatic
degradation by brush-border enzymes (Agarwal and Khan, 2001).
The application of mucoadhesive polymer has been proposed in present study
for making intimate contact with small intestine brush border layer that will
facilitate absorption as well as limit exposure of insulin to luminal contents.
Unlike colonic insulin delivery, the absorption of insulin from small intestine
will also prevent hyperinsulinemia condition which is being foreseen as a problem
in all other routes proposed for insulin delivery (Hsu et
al., 2007). In last few years, pectin, carbopols, polyvinyl alcohol
(PVA), chitosan and its derivatives (with thiol groups) and various other mucoadhesive
polymers have been checked for their potential in increasing oral bioavailability
of insulin. Out of these, chitosan derivatives like thiolated chitosan, poly(MAA-g-EG)
hydrogels have shown tremendous success in enhancing absorption (Hosny
et al., 2002; Bernkop-Schnürch, 2000,
2004; Krauland et al., 2004;
Mahkam, 2010). But chitosan and its derivatives have
not been still recognised as safe ingredients under GRAS (generally recognised
as safe) notifications. Furthermore, chitosan and its derivatives show pH dependent
mucoadhesive behaviour. In present study, we used GRAS notified polymer i.e.,
HPMC which is known for its pH independent mucoadhesive properties. HPMC matrix
tablets have shown slow and steady erosion type release of soluble drug molecules
in wide pH range (1.2 to 7.5) and most often macromolecules do also show similar
type of release from swellable matrices (Singh et al.,
HPMC is available in various viscosity grades ranging from very low viscosity
to very high viscosity; so, dependence of insulin absorption on viscosity has
been stressed in this work. Simultaneously, effect of substitution ratio has
also been tried to correlate with insulin absorption. The use of permeation
enhancers and/or enzyme inhibitors (Yamamoto et al.,
1994) was avoided due to several side effects associated with their own
absorption and chances of systemic intoxication (Krauland
et al., 2004). As HPMCs provided by Colorcon Asia Pvt. Ltd, India
were for non-clinical purpose only, so search was restricted to animal studies.
MATERIALS AND METHODS
Materials: Zinc insulin (particle size <1 μm, 1 IU = 0.035 mg, Novo Nordisk, India) ready for i.v. Injection purpose was used in present study. HPMCs (MethocelTM, Colorcon Asia Pvt. Ltd., India) and EudragitTM L100 and L100-55 (Röhm Pharma, Germany) were used as matrix polymer and coating polymers for granules preparation. The required phosphate buffers were prepared as per instructions of Indian Pharmacopoeia 1996 (IP96) using analytical grade chamicals from SD Fine chemicals, India and LobaChemie, India.
SugarchekTM glucometer (Wockhardt Ltd.), Hitachi U2800 spectrophotometer, LabIndia dissolution rate testing apparatus, Nichipette micro pipettes, Sartorius electronic balance LE324S etc., were basic instruments used at various stages in research. Sieves no. 22 (0.710 mm), 30 (0.500 mm) and 44 (0.355 mm) of BS standard were used for making and sorting granules. Blunt tip SS needles (No. 18; inner dia. 0.838 mm) covered with siliconized oral feeding tube (No.6) of approx. 1.5 inches length were used for rats oral gavage.
The in vitro studies were completed at Guru Nanak Dev University, Amritsar before 2006 end while animal studies completed in mid-2009 after taking all clearances form institutional ethics committee at Pt. BDS University of Health Sciences, Rohtak.
Concentrating insulin process: The concentrating process of zinc insulin
was carried out to adjust the insulin dose in a smallest feasible amount of
HPMC. Concentrated insulin was not stored to avoid any further stability related
studies. Various concentrating processes are known for concentrating insulin
like high-performance liquid chromatography, ultrafiltration, centrifugation
and even evaporation at various stages in industrial processes. The efficiency
of ultrafiltration and centrifugation are considered high compared to chromatography.
As we had to concentrate purified insulin only, so centrifugation process was
adopted. The modified industrial centrifugation process as per Datar and Rosen
was carried out using pooled suspensions of zinc insulin and a laboratory centrifuge
at 6500x g for 3 h (Datar and Rosen, 1990). Post-centrifugation,
the supernatant and concentrate (insulin phase) were analysed for insulin amounts
using Singh and Singh analytical method (Singh and Singh,
2009). The concentrating process was run thrice with 100 mL pooled quantity
each time to observe overall variation and effect on insulin assay value.
Selection of HPMC grades: As in Table 1, six grades
of HPMC among eleven grades (divided into 4 groups) provided by the Colorcon
Company were used in study covering wide viscosity range. Instead of referring
viscosity values each time in further sections, all the grades have been mentioned
with their corresponding grade names prefixed (E or K) and suffixed (LV or M)
appropriately as described by company.
|| Grouping of HPMC grades on viscosity and substitution ratio
|*Grades used for studies, # Actual reported values
by Colorcon Asia Pvt. Ltd, India for batches provided. Limits as per USP/
Ph Eur. :19.0-24.0% methoxyl, 7.0-12.0% hydroxypropyl for low substitution
ratio, 28.0-30.0% methoxyl, 7.0-12.0% hydroxypropyl for medium substitution
|| Composition of single oral doses* (for 150 g rat) used for
in vivo studies
|*Enteric coating resulted into additional 10% increase in
theoretical weight of granules
Selection of doses for in vivo studies: The per dose compositions of enteric coated HPMC-insulin granules (HPMC-insulin granules), enteric coated control granules (control granules or placebo) and the control (peroral) solution for average 150 g rat are listed in Table 2.
Preparation of granules: The sufficient quantities of concentrated zinc insulin and HPMC were mixed in multiples of one oral insulin dose as proposed in Table 2. The mixture was passed through a sieve set of 10-16-22 BS standard. The 16-22 sized granules after vacuum drying in a desiccator at normal lab temperature were compressed to big slugs by single punch tablet-making machine. The slugs were then crushed and sieved through a sieve set of 22-30-44 BS standard. Thereafter, the granular mass ranging between 30-40 sieves was enteric coated with 50:50% composition of Eudragit L100-55 and Eudragit L100 in a 3% w/v acetonic solution and air dried using lab developed fluid bed dryer at air pressure of 1.8±0.2 kg cm-2. Coating was continued until an average theoretical weight increase of ≈10% had been achieved. The purpose of enteric coating was to prevent insulin release in stomach and making effective release above pH 5.5 as L100-55 and L100 start dissolving within a pH range of 5.5-6.0. The enteric-coated granules were again sieved through 30-40 sieve set to get final granules between 0.355-0.500 mm size for oral administration to rats. The procedure was repeated similarly for preparation of other HPMC-insulin granules. The control granules were prepared of only E4M grade of HPMC without addition of insulin concentrate and using demineralized water as granulating agent.
Effect of granulation/coating process: As the claimed amount of zinc
insulin in single oral dose for 150 g rat was 0.788 mg (22.444 IU) and granules
were checked for this amount after granulation/coating process in phosphate
buffer of pH 7.0. The analytical method used was as standardised by Singh
and Singh (2009). The method was repeated in triplicate for HPMC-insulin
granules chosen randomly. The Mean±SD alongwith RSD of % assay were reported
to explain variance.
Preparation of insulin solutions for intravenous and subcutaneous injection: Intravenous and subcutaneous injections of zinc insulin suspension served as positive controls for absolute and relative pharmacological efficacies determination. For i.v. injection 0.035 mg kg-1 b.wt. (1 IU kg-1 b.wt.) and for s.c. injection 0.070 mg kg-1 b.wt. (2.0 IU kg-1 b.wt.) of insulin were dissolved to final makeup of 0.1 mL in sterile 154 mM phosphate buffered saline pH 7.5 previously filtered through G-5 sintered glass filter (1-2 μm, Borosil, India) and subsequently injected.
In vitro release studies: HPMC-insulin granules of four grades; E5LV, K100LV, E4M and K100M were subjected to in vitro dissolution studies in triplicate in pH 1.2 and 6.6. The paddle type dissolution rate testing apparatus complying with standards of IP96 was used. The release was reported as % insulin release (n = 3) from granules (equivalent to 450 IU insulin) in 500 mL of medium up to 8 h.
In vivo evaluation of granules: The animal studies were approved
by Institutional Animal Ethics Committee, PGIMS, Rohtak, India and adhered to
the guidelines of lab animal care. Non-diabetic, white albino rats of 150±10
g weight were purchased from approved source Hisar Agriculture University, Haryana.
Total 11 groups each consisting of 6 rats were used for in vivo studies.
Six groups received orally HPMC-insulin granules (each made of different HPMC
grade) at an insulin dose of 5.252 mg kg-1 b.wt. (150 IU kg-1
b.wt.), suspended in glycerine IP for easy administration. Four other groups
received s.c. injection/dose, i.v. Injection/dose, control (peroral) solution
and control granules for relative, absolute pharmacological reference and controls.
One group was kept as control (untreated). Blood samples were withdrawn from
tail vein immediately prior to administration of the dose as the t = 0 h value
and subsequently at 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 24 h post administration
of doses. Additional samplings at 0.5 h interval were done for i.v. and s.c.
injections/doses to note their early possibility of pharmacological response.
The dosed rats were fasted for 12 h and kept in cages with free access to water.
Blood glucose levels were immediately determined using the blood glucose reader
or glucometer (SugarCheck, Wockhardt, India) (Krauland et
al., 2004). The initial blood glucose levels were regarded as 100% and
all other levels referred to them as % of initial level.
The Area above Curve (AAC) values of plots of blood glucose against time were
calculated for each control and HPMC-insulin granules using control granules
(placebo) curve as baseline curve (Nakamura et al.,
2004). The relative pharmacological efficacy of insulin was determined as
the ratio of AAC (pharmacological) for oral dose and AAC (pharmacological) for
subcutaneous injections multiplied by ratio of s.c. dose and oral dose, whereas
absolute pharmacological efficacy was determined as the ratio of AAC (pharmacological)
for oral dose and AAC (Pharmacological) for intravenous injections multiplied
by ratio of i.v. dose and oral dose (Krauland et al.,
2004). So, relative pharmacological efficacy calculated referred to the
s.c. injection results, whereas the absolute pharmacological efficacy to i.v.
Statistical data analysis: The multiple comparisons post-hoc test, Least
Square Difference (LSD) was applied to explain the difference of grades (6 grades
as 6 groups) from each other and from controls (control (untreated) and control
(peroral)) (Norman and Streiner, 2008). A p-level of 0.05
was considered as the minimal level of significance. Calculations were done
using SPSS 16.0.1.
Concentrating insulin process: As in Table 3, the
overall yield (% Assay) for concentrate or insulin phase remained 78.3±0.3
(Mean±SD; n = 3) in our method which is very low compared to 99.5% step
yield of industrial process for insulin (Datar and Rosen,
1990). Net 9.5±0.2 (Mean±SD; n = 3), % loss was observed in
the process. The RSD for both yield and % loss was found less than 2.0% in an
overall process of centrifugation.
Effect of granulation/coating process: The actual theoretical weight increase observed was ranging between 9.8-11.5% on an overall for all the granules. Table 3 shows the insulin % assay values obtained for three randomly chosen samples of HPMC-insulin granules. The effect of granulation/coating process was minimal on insulin composition in granules as clear from 99.6% assay value. The RSD less than 2.0% also indicated good stability of insulin during granulation/coating process.
In vitro release studies: On an overall, no insulin release was observed in pH 1.2 up to 8 h from any of the four test HPMC-insulin granules. In pH 6.6 (Fig. 3), gradual increase in insulin release rate was observed for all the four grades. The insulin release >85% was observed during first 3.0 h for E5LV and K100 LV. In E4M and K100M this release was not observed even up to 4 h. All the grades showed almost complete (>85%) release upto last time point i.e., 8 h.
In vivo evaluation of granules: To confirm the usefulness of HPMC in increasing oral absorption of insulin, HPMC-insulin granules were tested in vivo in rats. In comparison, insulin was applied orally to rats in solution. Furthermore, insulin was injected intravenously and subcutaneously. The response as % change in blood glucose level w.r.t. initial level i.e., t = 0 h following the i.v., s.c. injections/doses and controls have been shown in Fig. 1. Similarly, the results as % change in blood glucose level w.r.t. initial level (t = 0 h) of the orally administered HPMC-insulin granules of different HPMC grades have been shown in Fig. 2.
In Fig. 2, HPMC-insulin granules led to different strength
of responses with significant to slight decrease in blood glucose levels except
K100M where almost no change observed. Among various grades, blood glucose lowering
effect is maximum for K100LV followed by E50LV and then E5LV.
|| Analytical data and amount recovered of insulin in centrifugation
and granulation/coating processes
|Each Conc. values is Mean±SD for n = 3 except dilution
factor. Equation applied for assay was AUAC = -0.009+71.112xConc. (Laboratory
developed standard equation; unpublished). @For centrifugation:
claimed amount in pooled qty (100 mL) was 4000 IU (140 mg) of zinc insulin,
# For granulation/ coating: claimed or labelled amount was 22.444
IU (0.788 mg) of zinc insulin
|| % Change in blood glucose levels for different controls or
|| % Change in blood glucose levels for HPMC-insulin granules
of various HPMC grades
|| In vitro release of insulin from various HPMC-insulin granules
in pH 6.6
|| Main pharmacokinetic parameters after administration of control
(peroral) solution, I.V. injection and S.C. Injection
|Values are Mean±SD (n = 6). *Acted as reference for
AAC (Area Above Curve) calculation for all other controls and grades under
||Main pharmacokinetic parameters after oral administration
of enteric coated hpmc-insulin granules of various HPMC grades
|Values are Mean±SD (n = 6)
The E4M is showing somewhat intermediary effect while K4M least effect. The
maximum pharmacological effect achieved is after 4 h with a decrease of blood
glucose level to 76.333±2.582% (Mean±SD; n = 6) in case of K100LV.
In all the cases, except K100M, blood glucose levels reached the initial levels
upto 24 h of dosage administration but not upto 10 h.
Various pharmacokinetic parameters derived from blood glucose vs. time profiles have been shown for controls (insulin containing) and HPMC-insulin granules in Table 4 and 5. Insulin given as control (peroral) solution did not show any significant effect and the blood glucose levels are in accordance to the normal physiological fluctuations of control (untreated). Pharmacological response after i.v. and s.c. injections had a minimum after 2 h and 1h with 46.116±5.456% and 39.909±2.600% of the initial blood glucose level, respectively. The effect, however, lasted only for 6 and 8 h (Fig. 1).
The maximum and minimum relative pharmacological efficacies are 1.399±0.138% (Mean±SD; n = 6) in case of K100LV and 0.292±0.031% (Mean±SD; n = 6) for K100M as compared to 0.040±0.024% (Mean±SD; n = 6) for control (peroral) solution and 100% for s.c. injection. Similarly, the maximum and minimum absolute pharmacological efficacies are 0.537±0.059% (Mean±SD; n = 6) for K100LV and 0.080±0.044% (Mean±SD; n = 6) for K100M as compared to 0.029±0.021% (Mean±SD; n = 6) for control (peroral) solution and 100% for i.v. injection. The values for both pharmacological efficacies are given in Table 4 and 5 for controls and grades. Thus K100LV increased absorption 35 times on relative basis and 18 times on absolute basis in comparison to control (peroral) solution indicating potential of K100LV in enhancing oral bioavailability of insulin. Depending upon this data the order may be presented primarily as:
The differences in grades and controls analysed statistically with multiple
group comparison, LSD test, at p-level of 0.05 using % of initial blood glucose
levels as response variables have been given in Table 6.
|| Post-Hoc (LSD) test for multiple comparisons between different
|*The mean difference is significant at the 0.05 level. Values
in parenthesis are significant for each comparison. @Control
(untreated). #Control soln. (peroral)
The values shown are mean difference values for grades/controls treated as
primary and secondary groups one by one. It is apparent from the data that significant
difference exists for K100LV, E50LV, E5LV, E4M-insulin granules from control
(untreated) and for K100LV, E50LV-insulin granules from control (peroral) solution.
This shows that K100LV and E50LV are significantly different from both controls
while E5LV and E4M are significantly different from only control (untreated).
Hence, K100LV and E50LV increased absorption remarkably while E5LV and E4M moderately.
The remaining K4M and K100M enhanced absorption upto so small extent that their
responses are not differing significantly even from control (untreated). Thus
order on basis of grades vs. controls may be spotted or categorised as:
For ease in understanding, the above order may be pronounced in terms of effect (blood glucose lowering) categories as remarkable effect category, moderate effect category and minor/ or no effect category.
Now after grades vs. controls comparison, the categorised grades may be analysed further for inter-grades comparison. At first the category showing remarkable effect includes, low viscosity, K100LV (Group II, K series) and low viscosity, E50LV (Group I, E series) grades (Table 1). The K100LV is showing significant difference from all grades except E50LV (significance value 0.118) but E50LV is having maximum similarity to E5LV (significant value of 0.186) (Table 6). So, both K100LV and E50LV may be treated as different response groups of remarkable effect category.
The second, moderate effect category also includes the very low viscosity,
E5LV (Group I, E series) and high viscosity, E4M (Group IV, E series) grades
(Table 1). E5LV is showing strongest similarity for E4M (significance
value of 0.388) and similarly E4M for E5LV (significant value of 0.388) (Table
|| Effect of HPMC viscosity and substitution ratio on Oral insulin
Thus responses of E5LV and E4M as grades may be considered equivalent i.e.,
E5LV≅E4M. This equivalence of individual grades shall not be confused with
Group equivalence i.e. Group I≠Group IV, as Group I is representing to large
E series, having E5LV as well as E50LV and in no way E4M is equivalent to E50LV.
However, such situation may be represented in brief as Group I≥Group IV in
producing response, as few grades may show similarity (like E5LV≅E4M) but
not all (like E50LV≠E4M in this study).
The minor effect category includes high viscosity, K4M (Group III, K series) and very high viscosity, K100M (Group III, K series) grades (Table 1). The K4M is showing maximum similarity to E4M (significance value 0.326) and K100M to K4M (significance value 0.260) (Table 6), so both are conforming to different response groups. The situation may be represented here as K4M>K100M.
Thus overall order in terms of grades and groups may be represented either as:
or correlated to viscosity and substitution ratio as in Table
The concentrating process was done with a laboratory centrifuge to adjust insulin
dose in smallest possible mass of HPMC. The process of concentrating by centrifugation
was not as efficient as industrial process described by Datar
and Rosen (1990) but adopted being fast and simple. Table
3 is showing the recovered quantity of zinc insulin after centrifugation.
The low % yield in our case may be due to use of laboratory centrifuge instead
of high-speed industrial centrifuge.
The effect of granulation/coating was minimal as from the data in Table
3 indicating good stability of insulin during process. The normal temperature
instead of high temperatures during process may be responsible for low insulin
degradation. Further, entrapment of zinc insulin in solid matrix carrier (HPMC)
may be a rational answer for stability of zinc insulin. The fast release of
insulin from E5LV, K100LV compared to E4M, K100M granules may be due to different
viscosity categories. The gel layer in former, due to low viscosity, might have
washed away easily which was otherwise tough to get eroded in later grades.
But on an overall, the results of insulin release were not widely different.
These results are consistent to previous findings of various researchers for
solid dosage formulations like pellets, tablets having higher concentrations
of HPMCs (Campos-Aldrete and Villafuerte-Robles, 1997;
Patel and Patel, 2007).
Figure 1, 2 and Table 4, 5 are showing
% lowering of blood glucose levels and pharmacological efficacies of administered
controls and HPMC-insulin granules. The relative pharmacological efficacy of
1.399±0.138% from K100LV granules versus 1.69±0.42% from thiolated
chitosan-insulin tablets reported by Krauland and co-workers (Krauland
et al., 2004) suggests almost equivalent potential of K100LV based
insulin granules in lowering blood glucose levels. However, this value is very
less compare to ≈8.0% relative pharmacological efficacy from P(MAA-g-EG)
hydrogels (Nakamura et al., 2004). The possible
reason may be the promotion of insulin absorption through paracellular pathway
by strong mucoadhesive complexation hydrogels (Kavimandan
and Peppas, 2008).
The insulin solutions administered directly into rat ileal segments have reported
relative bioavailability of 0.5±0.1% (Morishita et
al., 2004). In our case the relative pharmacological efficacy of 0.04±0.024%
indicates heavy degradation of insulin in control (peroral) solution from stomach
to small intestine. This also suggests strong protection of insulin in K100LV
granules which enhanced insulin absorption by 35 times relatively as compared
to control (peroral) solution. Relating different grades response (lowering
blood glucose) generates a general consolidated order in following manner:
This order is simple and does not explain similarity or dissimilarity in responses between two or more grades even if present. Further, the effect of viscosity and substitution ratio can only be explained if such similarity or dissimilarity of grades can be predicted. The LSD test provided sufficient analysis for grade vs. grades and grade vs. controls comparisons. The LSD test data was processed first as grades vs. controls and then grades vs. grades. This grades vs. controls comparison resulted into categorization of grades into remarkable, moderate and minor or null effect categories. The categories were represented as:
where, K100LV and E50LV belonged to remarkable effect category; E5LV and E4M to moderate effect category and K4M and K100M to minor effect category.
On grades vs. grades comparison basis the above order was resolved further to another order as:
and group wise as:
The reasons for low absorption from E5LV and E4M-granules may be the easy loss
of insulin by simple washouts from these very low viscosity grades and inability
of insulin to get released from gel matrix of high and very high viscosity grades
(K4M and K100M) granules. This inference is further supported by in vitro
dissolution studies, which showed fast insulin release from E5LV and delayed
release from both E4M and K100M based granules in pH 6.6. So, viscosity in both
cases may be responsible for lower pharmacological responses but nothing can
be said for substitution ratio effect. This statement is further supported from
ranking of K4M and K100M grades (high and very high viscosity) at last in blood
glucose lowering and pharmacological efficacies data (Fig. 2,
Table 5). This finding is in relevance to findings of Mesiha
and Sidhom studies of increase in insulin absorption by medium viscosity hydroxypropylcellulose
grade (Mesiha and Sidhom, 1995). The overall order of
HPMC grades along with viscosity and subtitution ratio has been represented
finally in Table 7.
The effect of substitution is not understandable and it can be said that viscosity masks the effect of substitution ratio. The effect of substitution ratio at very low and high viscosity ranges need further search.
As the low viscosity grades of HPMC featured good absorption enhancing properties. Being GRAS notified and known for pH independent behavior, drug delivery systems based on these will be more acceptable. Further studies with wide range of viscosity and medium to low substitution ratio for same viscosity shall be tried.
We hereby acknowledge the help provided by Colorcon Asia Pvt. Ltd, India for providing gift samples of various grades of HPMCs required for the accomplishment of this project. This is a part study of the project sanctioned by Indian Council of Medical Research, New Delhi, India and we feel great to acknowledge the name of so also.