GB2480472A - Procarbazine hydrochloride capsules - Google Patents
Procarbazine hydrochloride capsules Download PDFInfo
- Publication number
- GB2480472A GB2480472A GB1008388A GB201008388A GB2480472A GB 2480472 A GB2480472 A GB 2480472A GB 1008388 A GB1008388 A GB 1008388A GB 201008388 A GB201008388 A GB 201008388A GB 2480472 A GB2480472 A GB 2480472A
- Authority
- GB
- United Kingdom
- Prior art keywords
- capsule
- approximately
- procarbazine hydrochloride
- starch
- procarbazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 40
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960001586 procarbazine hydrochloride Drugs 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 229920000881 Modified starch Polymers 0.000 claims abstract description 14
- 229920002261 Corn starch Polymers 0.000 claims abstract description 12
- 239000008120 corn starch Substances 0.000 claims abstract description 12
- 239000001828 Gelatine Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 description 15
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 15
- 229960000624 procarbazine Drugs 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 239000007963 capsule composition Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 229940087732 matulane Drugs 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940071690 procarbazine 50 mg Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical capsule comprises only procarbazine hydrochloride and a mixture of coprocessed corn starch and pregelatinised starch. Preferably, the weight ratio of procarbazine hydrochloride to the mixture of co-processed corn starch and pregelatinised starch is approximately 1:2, wherein preferably the capsule has a total weight from 220 to 280mg and a fill weight from 162 to 198mg. Preferably, the capsule comprises approximately 58mg of procarbazine hydrochloride.
Description
INTELLECTUAL
. .... PROPERTY OFFICE Application No. GB 1008388.9 RTM Date:17 September 2010 The following terms are registered trademarks and should be read as such wherever they occur in this document: Starcap Intellectual Property Office is an operating name of the Patent Office www.ipo.gov.uk "A formulation"
Introduction
The invention relates to a pharmaceutical formulation comprising procarbazine hydrochloride.
Procarbazine is a hydrazine derivative antineoplastic agent. It is chemically described as n-( 1-methylethyl)-4-[(2-methylhydrazino) methyl] benzamide monohydrochloride, and is used for treating stage III and IV Hodgkin's disease.
The information available on the currently marketed capsule formulation of procarbazine hydrochloride suggests that the formulation comprises procarbazine hydrochloride, con starch (a filler), mannitol (a granulating agent), talc (a lubricant and glidant) in gelatine capsule shells.
This product is marketed under the Trade Mark Matulane.
There is a need for an improved formulation of procarbazine hydrochloride which will provide increased benefits for patients.
Statements of Invention
According to the invention there is provided a capsule containing only procarbazine hydrochloride and a mixture of co-processed con starch and pregelatinised starch.
In the manufacture of oral solid dose pharmaceutical products, excipients suchs as fillers, granulating agents, binders, lubricants and glidants are commonly employed. However, we have surprisingly found that the replacement of these components by a co-processed starch containing con starch and pregelatinised starch in a capsule formulation containing Procarbazine results in a product with excellent homogeneity of content, dissolution rate and impurity profile. The improvement in impurity profile is partially unexpected and important. Furthermore the resulting product can be readily manufactured and remains stable with lower impurity levels present. An additional benefit is that the product does not contain mannitol. Mannitol is a sugar alcohol that is derived from a sugar by reduction. The absence of mannitol in the capsule formulation of the invention may provide additional benefits to patients who suffer from diabetes.
In one embodiment the total weight of the capsule is from 220 to 280mg and the flu weigilt is from 162 to 198mg.
In one embodiment the capsule has a total weight of approximately 25 0mg and a fill weight of approximately 180mg.
In one case the weight ratio of the procarbazine hydrochloride to the mixture of co-processed corn starch and pregelatinised starch is approximately 1:2.
In one embodiment the capsule contains approximately 120mg of the mixture of co-processed corn starch and pregelatinised starch.
In one embodiment the capsule contains approximately 58mg of procarbazine hydrochloride.
The invention also provides a hard gelatine capsule having a total weight of approximately 0mg and containing only procarbazine hydrochloride and a mixture of co-processed corn starch and pregelatinised starch in a weight ratio of approximately 1:2.
Brief Description of the Drawings
The invention will be more clearly understood from the following description of an embodiment thereof, given by way of example only, with reference to the accompanying drawings, in which: Fig. 1 illustrates dissolution release profiles for two different capsule formulations; and Fig. 2 illustrates dissolution release profiles for two different capsule formulations.
Detailed Description
Example 1 -Capsule formulation according to the invention A hard gelatine capsule size 2 (capsule empty shell weight approximately 64mg) was filled with procarbazine hydrochloride and a co-processed mixture of corn starch and pregelatinised starch.
The total capsule weight was approximately 250mg and contained approximately 58mg of procarbazine hydrochloride (equivalent to approximately 50 mg of procarbazine) and approximately 122mg of the starch mixture. The weight ratio of procarbazine hydrochloride to the mixture co-processed corn starch and pregelatinised starch is 2.09:1.
Starcap 1500 is a non-compendial co-processed excipient mixture which is produced from two compendial grade excipients (corn starch and pregelatinised starch) using purified water in the manufacturing process.
We have surprisingly found that the inclusion of Starcap 1500 in the formulation of the invention performed equally as well as the established formulation which contains several excipients.
The appearance of the procarbazine capsules of the invention compared to the commercial 50 mg capsules is outlined in Table 1.
Procarbazine capsules Procarbazine 50 mg Parameter Procarbazine Hydrochloride Capsules Capsules, USP 50 mg (New) (Marketed) Shape Elongated Elongated Color Yellow Yellow Length 17.7 mm 17.2mm Capsule size 2 2 Total Capsule 248.6mg 402mg weight We have found that the capsules of the invention provided greater levels of blend uniformity. In this case, approximately a 250 mg capsule weight was sufficient to hold 50 mg of procarbazine compared to the capsule weight of 402 mg to cater for 50 mg of procarbazine in the known formulation.
Example 2 -Dissolution We have found that there are comparable release profiles between a batch (DTO4O) of capsules according to the invention and the Reference Listed Brand Drug (RLD). The dissolution profile shows that batch DTO4O achieved a release of 110.7% after 60 minutes while the RLD achieved a release of 105.4% after 60 minutes.
Table 2: Dissolution data for trial batch DTO4O Vs Commercial Lot No 04222A DTO4O 04222A Time 1mm Mean Mean %RSD %RSD _________ (n=6) _______ (n=3) _______ 0 0 -0 - 102.9 1.60 86.9 15.44 107.3 0.54 99.5 5.76 107.7 2.31 106.9 10.73 109.6 0.63 105.4 3.69 110.7 0.76 105.4 3.69 This data is graphically presented in Fig. 1.
In recent years, FDA (US Food and Drug Administration) has placed more emphasis on a dissolution profile comparison, as under appropriate test conditions, a dissolution profile can characterize the product more precisely than a single point dissolution test. In dissolution profile comparisons, especially to assure similarity in product performance, regulatory interest is in knowing how similar the two curves are, and to have a measure which is more sensitive to large differences at any particular time point. For this reason, the F2 comparison has been the focus in the US Agency guidance's. The factor F2 measures the closeness between the two profiles and when the two profiles are identical, F2 = 100. An average difference of 10% at all measured time-points results in a F2 value of 50. The FDA has set a public standard of F2 value between and 100 to indicate similarity between two dissolution profiles.
An F2 similarity factor of 59 was calculated (F2 between 50 and 100 indicates that the release profiles are similar). The dissolution profile of DTO4O was similar to the RLD lot # 04222A.
Example 3 -Manufacture of large scale batch Method of manufacture 1. The procarbazine hydrochloride was premixed with approximately half of the dispensed StarCap 1500, passed through a screen and collected in an Intermediate Bulk Container 2. The screen was flushed with the remaining StarCap 1500 and collected.
3. The contents of the Intermediate Bulk Container were blended until the contents are uniform.
Capsules were filled to a target fill weight of 180mg and encapsulated. The capsules produced were assigned the batch number S0014.
Table 3: Composition of batch number S0014 (Batch Size: 22.5kg) Component mg/capsule % w/w (filled) Procarbazine Hydrochloride 58.24 32.4 StarCap 1500 121.76 67.6 Hard Gelatin capsules 64.0 N/A Table 4: Dissolution profile of batch S0014 Time Vessel Number Mean % (mins) _____ _____ _____ ______ _____ _____ _____ _____ _____ _____ _____ 12 0 RSD 83.7 89.4 87.7 92.1 88.5 102.2 93.9 88.6 96.0 97.6 96.5 92.5 92.4 5.56 92.1 96.4 95.1 100.1 97.5 106.8 98.6 92.9 99.6 102.5 103.4 98.0 98.6 4.33 97.0 100.0 99.5 101.5 98.9 106.4 100.3 96.0 101.1 104.2 102.5 98.6 100.5 2.91 100.0 101.1 101.3 102.3 99.9 105.8 100.5 96.9 102.3 105.4 103.4 99.1 101.5 2.52 100.0 102.2 103.3 101.8 100.8 106.4 102.1 99.2 103.8 104.9 104.3 101.0 102.5 2.09 Table 5: Dissolution data for batch Lot # S0014 Vs RLD 50mg, Lot # B070087 under USP conditions (900 mls water at 37°C -50rpm -paddles)
________ _________________ ___________________
S0014 B070087 Time I Minutes (n=12) RSD (ii=12) % RSD 92.4 5.56 75.3 11.48 98.6 4.33 94.8 4.09 100.5 2.91 97.2 3.18 101.5 2.52 98.2 2.46 102.5 2.09 99.0 2.52 This data is presented graphically in Fig. 2.
Dissolution performed as per USP compendial conditions, as described in above as shown, there were comparable release profiles between batch S0014 and the RLD batch B070087 under USP conditions. The dissolution profile shows that batch S0014 achieved a release of 102.5% after 60 minutes while the RLD achieved a release of 99.0% after 60 minutes. An F2 similarity factor of 54 was calculated; an F2 between 50 and 100 indicates that the release profiles are similar.
During processing, 10 unit dose samples were taken from the final blend and evaluated for homogeneity. Lot No S0014 was comprehensively characterized with respect to particle size, hardness range, capsule press speed and uniformity of dose.
These results are favourable when compared to the data generated for RLD batch B070087 reference product.
Table 6: Assay data (S0014 and Matulane® B070087)
___________________________________________
S0014 Matulane® % Assay B070087 101.8 99.8 Table 7: Related substances data (S0014 and Matulane® B070087) Matulane® S0014 B070087 % Largest 0 08 1 00 Unidentified Impurity ______ __________ % Impurity B 0.04 N/A % Total impurities 0.17 1.58 Surprisingly significantly better initial impurity profiles for the capsule formulation according to the invention (Total Impurities: 0.17%) versus the established formulation 1.58%). This is particularly important because greater levels of impurities offer increased risks of side effects to the patient after administration of the medicine. However these risks are reduced in the invention because there are significantly lower levels of impurites present.
Blend Uniformity In order to verify the appropriate blend time of 20 minutes at 15 rpm, ten unit dose blend samples from batch S0014 were taken from several blender locations and evaluated for homogeneity. The data is presented in table 8 below.
Table 8: Blend uniformity results after 10 minutes blending (Batch S0014) Sample % Procarbazine % Procarbazine (After 10 minutes) (After 20 minutes) 1 99.7% 97.8% 2 100.0% 100.6% 3 101.2% 98.1% 4 101.5% 100.9% 100.7% 100.4% 6 101.4% 101.7% 7 100.9% 96.9% 8 100.4% 100.0% 9 98.9% 97.3% 101.1% 99.1% Mean 100.6% 99.3% RSD 0.8% 1.7% Minimum 98.9% 96.9% Maximum 101.5% 101.7% It can be seen from the resulting blend data, that the manufacturing process exhibits excellent homogeneity during processing. All results after 10 and 20 minutes blending were within ± 10% of the mean and the %RSD is below 5.0%.
The batch, S0014, was also evaluated for content uniformity using stratified in process unit dose sampling based on the proposal in FDA Draft Guidance for Industry "Powder Blends and Finished Dosage Unity-StratifIed In-Process Dosage Unit Sampling and Assessment" In this case; three capsules were evaluated for content uniformity at 20 different locations throughout the manufacturing run. The data are presented in the table below.
Table 9: Uniformity of content (Stratified testing) -S0014 Sample A B C Average 1 100.7% 97.8% 101.8% 100.1% 2 103.1% 102.3% 103.5% 103.0% 3 102.8% 101.3% 101.1% 101.7% 4 102.2% 101.3% 101.7% 101.7% 101.2% 103.2% 101.3% 101.9% 6 103.5% 101.4% 101.2% 102.0% 7 103.5% 102.8% 101.9% 102.7% 8 102.0% 102.6% 100.6% 101.7% 9 100.9% 103.2% 102.1% 102.1% 102.4% 98.3% 99.5% 100.1% 11 106.9% 103.0% 103.0% 104.3% 12 100.9% 102.3% 103.7% 102.3% 13 104.2% 101.9% 100.2% 102.1% 14 100.3% 100.9% 99.8% 100.3% 101.8% 104.1% 102.0% 102.6% 16 106.9% 104.9% 102.8% 104.9% 17 104.2% 103.5% 101.7% 103.2% 18 100.7% 100.4% 101.5% 100.9% 19 101.3% 102.9% 101.9% 102.0% 100.6% 101.5% 102.0% 101.4% Mean (%) 102.1% Minimum (%) 100.1% Maximum (%) 104.9% %RSD 1.2% The %RSD of the individual stratified sample data is below 4.0% and each location mean is within 90.0 -110.0 % of the target potency. Furthermore, all individual results are within 75.0% to 125.0% of the target potency. As a result, the stratified content uniformity meet the "readily pass criteria" of the FDA draft guidance.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (8)
- Claims 1. A pharmaceutical capsule containing only procarbazine hydrochloride and a mixture of co-processed corn starch and pregelatinised starch.
- 2. A capsule as claimed in claim 1 wherein the total weight of the capsule is from 220 to 28 0mg and the fill weight is from 162 to 198mg.
- 3. A capsule as claimed in claim 1 or 2 wherein the capsule has a total weight of approximately 25 0mg and a fill weight of approximately 180 mg
- 4. A capsule as claimed in any of claims 1 to 3 wherein the weight ratio of the procarbazine hydrochloride to the mixture of co-processed corn starch and pregelatinised starch is approximately 1:2.
- 5. A capsule as claimed in any of claims 1 to 4 containing approximately 120mg of the mixture of co-processed corn starch and pregelatinised starch.
- 6. A capsule as claimed in any of claims 1 to 5 containing approximately 58mg of procarbazine hydrochloride.
- 7. A hard gelatine capsule having a total weight of approximately 250mg, a fill weight of mg and containing only procarbazine hydrochloride and a mixture of co-processed corn starch and pregelatinised starch in a weight ratio of approximately 1:2.
- 8. A capsule substantially as hereinbefore described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1008388.9A GB2480472B (en) | 2010-05-20 | 2010-05-20 | A procarbazine hydrochloride formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1008388.9A GB2480472B (en) | 2010-05-20 | 2010-05-20 | A procarbazine hydrochloride formulation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB201008388D0 GB201008388D0 (en) | 2010-07-07 |
| GB2480472A true GB2480472A (en) | 2011-11-23 |
| GB2480472B GB2480472B (en) | 2017-05-10 |
Family
ID=42341019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1008388.9A Active GB2480472B (en) | 2010-05-20 | 2010-05-20 | A procarbazine hydrochloride formulation |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2480472B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB968460A (en) * | 1961-06-09 | 1964-09-02 | Hoffmann La Roche | Novel hydrazine derivatives and a process for the manufacture thereof |
| US3931268A (en) * | 1961-06-09 | 1976-01-06 | Hoffmann-La Roche Inc. | Methylhydrazinomethyl-substituted benzoic acid amides |
-
2010
- 2010-05-20 GB GB1008388.9A patent/GB2480472B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB968460A (en) * | 1961-06-09 | 1964-09-02 | Hoffmann La Roche | Novel hydrazine derivatives and a process for the manufacture thereof |
| US3931268A (en) * | 1961-06-09 | 1976-01-06 | Hoffmann-La Roche Inc. | Methylhydrazinomethyl-substituted benzoic acid amides |
Non-Patent Citations (2)
| Title |
|---|
| Sigma-Tau Pharmaceuticals, matulane capsules, Available from http://matulane.com/pdf/prescribe-info.pdf [Accessed 14 September 2010] * |
| The Electronic Medicines Compendium (eMC) [online], Alliance Pharmaceuticals, procarbazine capsules, Available from http://www.medicines.org.uk/emc/medicine/386/SPC/procarbazine%20capsules%2050mg/nhsevidenceàexcipients [Accessed 14 September 2010] * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201008388D0 (en) | 2010-07-07 |
| GB2480472B (en) | 2017-05-10 |
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